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Aims: Infections have been associated with acute myocardial infarction (AMI), but differences in risk between infection types and age groups are unclear. This study aims to investigate whether infections are associated with subsequent AMI and whether the risk differs across infection sites and age groups., Methods: Nationwide registers were used to include 702596 adults hospitalized between 1987-2018 with either; pneumonia (n=344319), urinary tract infection (UTI) (n=270101), soft tissue/bone infection (n=66718), central nervous system infection (CNS) (n=17025), or endocarditis (n=4433). Patients were sex- and age-matched with two unexposed controls. Outcome was first-time AMI within ten years. A time-dependent cox proportional hazards model with cut-offs at 30 and 90 days was used for calculating adjusted hazard ratios (HR)., Results: Pneumonia, UTI, and soft tissue/bone infection were associated with increased relative rates of AMI compared to matched, unexposed controls. Highest relative rates were found within the first 0-30 days post-exposure; Pneumonia: HR 3.39 (95% CI 3.15-3.65), UTI: HR 2.44 (95% CI 2.21-2.70), Soft tissue/bone infection: HR 1.84 (95% CI 1.45-2.33). Relative rates decreased over time but remained significantly elevated throughout the follow-up period and was increased in all age groups. No association was found for CNS infection and for endocarditis only at 31-90 days, HR 2.28 (95% CI 1.20-4.33)., Conclusion: Acute infections are associated with increased relative rates of AMI across different infection sites and age groups with higher relative rates found for pneumonia. This indicates that some infections may act as a trigger for AMI with a site and/or pathogen specific risk., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Aims: To assess the risk of anaemia among low-dose aspirin (LDA) exposure in Danish older individuals in a real-world setting., Methods: Population based-cohort study conducted using Danish registers. The study population included older individuals (≥65 years) exposed to LDA between 2008 and 2013 for primary or secondary prevention of cardiovascular events. Over a five-year follow-up, outcomes included anaemia incidence based on haemoglobin values and hematinic deficiency incidence based on antianemic prescriptions., Results: Among the 313 508 individuals included in the study population, those exposed to LDA (n = 59 869, 19.1%) had an incidence of hematinic deficiency determined by the use of antianemic treatment of 9.6%, with an incidence rate ratio of 9.11 (95% Confidence Interval, CI: 8.81-9.41) when compared to non-users of LDA (n = 253 639, 80.9%), who had an incidence of 3.7%. Anaemia determined by haemoglobin value measurements was observed in 5.9% of those exposed to LDA, with an incidence rate ratio of 7.89 (95% CI: 7.58-8.21) when compared to non-users of LDA. Approximately one in five individuals (n = 2 422, 21.5%) who experienced anaemia also experienced bleeding. Severe anaemia was observed in 1.3% of those exposed to LDA compared to 0.6% of those not exposed. Among the exposed, the reduction in haemoglobin and ferritin levels was associated with the severity of anaemia., Conclusion: These findings indicate that in a real-world setting, anaemia with LDA can occur in 6 to 10 older individuals out of every 100 LDA users during the first 5 years of treatment., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Background: The influence of age on cardiac troponin is unclear and may vary between cardiac troponin T (cTnT) and I (cTnI). We aimed to compare the impact of age on the diagnostic and prognostic utility of cTnT and cTnI., Methods: This Danish nationwide, register-based cohort study included patients with at least one cardiac troponin (cTn) measurement from 2009 through June 2022, stratified into decades of age. We used peak cTn concentration during admission, dichotomized as positive/negative and normalized to the 99th percentile. Receiver operating characteristics for myocardial infarction (MI) and logistic regression were used to estimate the odds ratio (OR) for mortality at 1 year., Results: We included 541 817 patients; median age 66 years (interquartile range [IQR] 51-77) and 256 545 (47%) female. A total of 40 359 (7.4%) had an MI, and 59 800 (14.1%) patients died within 1 year of admission. The predictive ability of both cTns for MI were highest for patients 30 to 50 years. This was most pronounced for cTnT, the specificity of which fell from 83% among patients 40 to 49 years to 4% for patients ≥90 years. The prognostic ability of both cTns for 1-year mortality declined with age. cTnT had stronger prognostic ability for all age-groups; OR for a positive cTnT 28.4 (95% CI, 20.1-41.0) compared with 9.4 (95% CI, 5.0-16.7) for cTnI among patients <30 years., Conclusions: The predictive and prognostic ability of cTnT and cTnI declined with age. cTnT had a low specificity for MI in elderly patients. However, cTnT was the strongest prognostic marker among all age groups., (© Association for Diagnostics & Laboratory Medicine 2024. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Background and Aims: In patients undergoing heart valve surgery, subsequent bacteremia and infective endocarditis are feared events. Data on the incidence and bacterial microbiological etiology following left-sided heart valve surgery are sparse., Methods: Between 2010-2021, all patients undergoing left-sided valve surgery were identified using Danish nationwide registries. Incidence and type bacteremia within one-year post-surgery was analyzed. Secondary outcome of interest was infective endocarditis. Cumulative incidence curves were stratified for bacterial species and for subgroups of interest: type of valve surgery, age, and sex., Results: A total of 14 935 patients were included, of which 69% were male and the median age was 70.4 years (25th-75th percentile 62.4-76.2 years). The one-year cumulative incidence of bacteremia was 6.1% (95% CI 5.7-6.5%), and the most frequent bacteremia was coagulase-negative staphylococci (27%). More than half of the bacteremia with coagulase-negative staphylococci occurred within 30 days of follow-up. Patients developing bacteremia had a significantly higher Charlson comorbidity score at baseline, more often underwent CABG concomitant to valve surgery, and more often had surgery on both valves. The one-year cumulative incidence of infective endocarditis was 1.5% (95% CI 1.3-1.7), of which 23% were caused by Enterococci, and 22% were blood culture negative. The median time from surgery to infective endocarditis was 109 days., Conclusions: Bacteremia and infective endocarditis following left-sided heart valve surgery occurred in 6.1% and 1.5% of patients, respectively. The most frequent bacteremia was coagulase-negative staphylococci, and more than half of these occurred within 30 days of surgery. Optimization of prophylactic strategies are warranted., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Background: Sex- and population-specific 99th percentiles of high-sensitivity cardiac troponin (hs-cTn) are recommended in guidelines although the evidence for a clinical utility is sparse. The DANSPOT trial will investigate the clinical effect of sex- and population-specific 99th percentiles of cTn. We report the 99th percentiles derived from this trial and their dependency on kidney function., Methods: We used samples from healthy Danish blood donors and measured hemoglobin A1c, N-terminal pro-brain natriuretic peptide and creatinine, and calculated an estimated glomerular filtration rate (eGFR). We compared 2 cutoffs for the eGFR of healthy participants (60 vs 90 mL/min/1.73 m2). The cTn assays investigated were Siemens Atellica and Dimension Vista hs-cTnI, Abbott hs-cTnI, and Roche hs-cTnT., Results: A total of 2287 participants were sampled, of which 71 (3.1%) were excluded due to a history of heart disease (n = 4), insufficient material (n = 7), or a screening biomarker (n = 60). Of the remaining 2216 participants, 1325 (59.8%) had an eGFR ≥90 mL/min/1.73 m2. Compared to a cutoff of 60 mL/min/1.73 m2 for eGFR, using 90 mL/min/1.73 m2 resulted in lower 99th percentiles for females; Siemens Vista (46 vs 70 ng/L), Abbott (14 vs 18 ng/L), and Roche cTnT (10 vs 13 ng/L), and decreased the number of measurements above the manufacturers' 99th percentiles for all assays., Conclusions: We present reference values for 4 cTn assays for eGFR cutoffs of 60 and 90 mL/min/1.73 m2. These cutoffs differ based on the eGFR threshold for inclusion indicating that any chosen cutoff is also valuable with moderately reduced kidney function., (© Association for Diagnostics & Laboratory Medicine 2024. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Objectives: Current guidelines provide limited evidence for cardiovascular screening in ANCA-associated vasculitis (AAV). This study aimed to investigate the prevalence of electrocardiogram (ECG) abnormalities and associations between no, minor or major ECG abnormalities with cardiovascular mortality in AAV patients compared with matched controls., Method: Using a risk-set matched cohort design, patients diagnosed with granulomatosis with polyangiitis or microscopic polyangiitis with digital ECGs were identified from Danish registers from 2000-2021. Patients were matched 1:3 to controls without AAV on age, sex, and year of ECG measurement. Associated hazards of cardiovascular mortality according to ECG abnormalities were assessed in Cox regression models adjusted for age, sex, and comorbidities, with subsequent computation of 5-year risk of cardiovascular mortality standardized to the age- and sex-distribution of the sample., Results: A total of 1431 AAV patients were included (median age: 69 years, 52.3% male). Median follow-up was 4.8 years. AAV was associated with higher prevalence of left ventricular hypertrophy (17.5% vs 12.5%), ST-T deviations (10.1% vs 7.1%), atrial fibrillation (9.6% vs 7.5%), and QTc prolongation (5.9% vs 3.6%). Only AAV patients with major ECG abnormalities demonstrated significantly elevated risk of cardiovascular mortality [HR 1.99 (1.49-2.65)] compared with controls. This corresponded to a 5-year risk of cardiovascular mortality of 19.14% (16-22%) vs 9.41% (8-11%)., Conclusion: Patients with AAV demonstrated a higher prevalence of major ECG abnormalities than controls. Notably, major ECG abnormalities were associated with a significantly increased risk of cardiovascular mortality. These results advocate for the inclusion of ECG assessment into routine clinical care for AAV patients., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Recent studies have shown that anticholinergic medications are associated with cardiovascular disease. Little is known about how discontinuation of anticholinergic medication affects this association. We investigated how baseline anticholinergic load and change in anticholinergic load associates with major adverse cardiovascular events (MACE) on four different scales., Methods: We included all geriatric outpatients aged 65 and older in Denmark between January 2011 and December 2018. Data were sourced from Danish national registries. Anticholinergic drug exposure was assessed at first contact to the outpatient clinic (baseline) and changes were assessed at 180 days after outpatient contact. Anticholinergic scales were the CRIDECO Anticholinergic Load Scale, Anticholinergic Drugs Scale, Anticholinergic Cognitive Burden and a scale by the Danish Institute of Rational Pharmacotherapy. Multivariate analyses were conducted to investigate the 1- and 5-year risk of MACE by baseline anticholinergic load and changes in anticholinergic load after 180 days., Results: We included a total of 64 378 patients in the analysis of baseline anticholinergic load and 54 010 patients remained after 180 days for inclusion in the analysis of change in anticholinergic load. At baseline the mean age was 81.7 year (SD 7.5) and 68% were women. Higher level of anticholinergic load on any scale associated with greater risk of MACE in a dose response pattern. There were no association between reduction in anticholinergic load and risk of MACE., Conclusion: While anticholinergic load at baseline was associated with MACE, reducing anticholinergic load did not lower the risk of MACE indicating the association may not be causal., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Geriatrics Society. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background and Aims: Patients with atrial fibrillation (AF) are at increased risks of cardiovascular diseases and mortality, but risks according to age at diagnosis have not been reported. This study investigated age-specific risks of outcomes among patients with AF and the background population., Methods: This nationwide population-based cohort study included patients with AF and controls without outcomes by the application of exposure density matching on the basis of sex, year of birth, and index date. The absolute risks and hazard rates were stratified by age groups and assessed using competing risk survival analyses and Cox regression models, respectively. The expected differences in residual life years among participants were estimated., Results: The study included 216 579 AF patients from year 2000 to 2020 and 866 316 controls. The mean follow-up time was 7.9 years. Comparing AF patients with matched controls, the hazard ratios among individuals ≤50 years was 8.90 [95% confidence interval (CI), 7.17-11.0] for cardiomyopathy, 8.64 (95% CI, 7.74-9.64) for heart failure, 2.18 (95% CI, 1.89-2.52) for ischaemic stroke, and 2.74 (95% CI, 2.53-2.96) for mortality. The expected average loss of life years among individuals ≤50 years was 9.2 years (95% CI, 9.0-9.3) years. The estimates decreased with older age., Conclusions: The findings show that earlier diagnosis of AF is associated with a higher hazard ratio of subsequent myocardial disease and shorter life expectancy. Further studies are needed to determine causality and whether AF could be used as a risk marker among particularly younger patients., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Background and Aim: There are a paucity of studies investigating workforce affiliation in connection with first-time implantable cardioverter defibrillator (ICD)-implantation. This study explored workforce affiliation and risk markers associated with not returning to work in patients with ICDs., Methods: Using the nationwide Danish registers, patients with a first-time ICD-implantation between 2007 and 2017 and of working age (30-65 years) were identified. Descriptive statistic and logistic regression models were used to describe workforce affiliation and to estimate risk markers associated with not returning to work, respectively. All analyses were stratified by indication for implantation (primary and secondary prevention)., Results: Of the 4659 ICD-patients of working age, 3300 patients (71%) were members of the workforce (employed, on sick leave or unemployed) (primary: 1428 (43%); secondary:1872 (57%)). At baseline, 842 primary and 1477 secondary prevention ICD-patients were employed. Of those employed at baseline, 81% primary and 75% secondary prevention ICD-patients returned to work within 1 year, whereof more than 80% remained employed the following year. Among patients receiving sick leave benefits at baseline, 25% were employed after 1 year. Risk markers of not returning to work were 'younger age' in primary prevention ICD-patients, while 'female sex', left ventricular ejection fraction 'LVEF ≤40', 'lower income', and '≥3 comorbidities' were risk markers in secondary prevention ICD-patients. Lower educational level was a risk marker in both patient groups., Conclusion: High return-to-work proportions following ICD-implantation, with a subsequent high level of employment maintenance were found. Several significant risk markers of not returning to work were identified including 'lower educational level' that posed a risk in both patient groups., Trial Registration Number: Capital Region of Denmark, P-2019-051., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Background and Aims: Coronary computed tomography angiography (CCTA) can guide downstream preventive treatment and improve patient prognosis, but its use in relation to education level remains unexplored., Methods: This nationwide register-based cohort study assessed all residents in Denmark between 2008 and 2018 without coronary artery disease (CAD) and 50-80 years of age (n = 1 469 724). Residents were divided according to four levels of education: low, lower-mid, higher-mid, and high. Outcomes were CCTA, functional testing, invasive coronary angiography (ICA), revascularization, and major adverse cardiovascular and cerebrovascular events (MACCE)., Results: Individuals with the lowest education level underwent CCTA (absolute risk [AR] 3.95% individuals aged ≥50-59, AR 3.62% individuals aged ≥60-69, and AR 2.19% individuals aged ≥70-80) less often than individuals of lower-mid (AR 4.16%, AR 3.90%, and AR 2.41%), higher-mid (AR 4.38%, AR 4.30%, and AR 2.45%) and highest education level (AR 3.98%, AR 4.37%, and AR 2.30%). Similar differences were observed for functional testing. Conversely, use of ICA, and risks of revascularization and MACCE were more common among individuals of lowest education level. Among patients examined with CCTA (n = 50 234), patients of lowest education level less often underwent functional testing and more likely initiated preventive medication, underwent ICA, revascularization, and experienced MACCE., Conclusion: Despite tax-financed healthcare in Denmark, individuals of lowest education level were less likely to undergo CCTA and functional testing than persons of higher education level. Invasive coronary angiography utilization, revascularization, and MACCE risks were higher for individuals of lowest education level. Among CCTA-examined patients, patients of lowest education level were more likely to initiate preventive medication and had the highest risks of revascularization and MACCE when compared to higher education level groups. These findings suggest that the preventive potential of CCTA is underutilized in individuals of lower education level, a proxy for socioeconomic status. Socioeconomic differences in CAD assessment, care, and outcomes are likely even larger without tax-financed healthcare., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Background and Aims: Patients with severely reduced kidney function have been excluded from randomized controlled trials and data on the safety and efficacy of direct oral anticoagulants (DOACs) according to kidney function remain sparse. The aim was to evaluate the safety and efficacy of the DOACs across subgroups of kidney function., Methods: Using multiple Danish nationwide registers and laboratory databases, we included patients initiated on oral anticoagulants (OACs) with atrial fibrillation and available creatinine level and followed patients for 2 years to evaluate occurrence of stroke/thromboembolism (TE) and major bleeding., Results: Among 26 686 included patients, 3667 (13.7%) had an estimated glomerular filtration rate (eGFR) of 30-49 mL/min/1.73 m2 and 596 (2.2%) had an eGFR below 30 mL/min/1.73 m2. We found no evidence of differences regarding the risk of stroke/TE between the OACs (P-value interaction >0.05 for all). Apixaban was associated with a lower 2-year risk of major bleeding compared to vitamin K antagonists (VKA) [hazard ratio 0.79, 95% confidence interval (CI) 0.67-0.93], and the risk difference was significantly larger among patients with reduced kidney function (P-value interaction 0.018). Rivaroxaban was associated with a higher risk of bleeding compared to apixaban (hazard ratio 1.78, 95%CI 1.32-2.39) among patients with eGFR 30-49 mL/min/1.73 m2., Conclusions: Overall, we found no differences regarding the risk of stroke/TE, but apixaban was associated with a 21% lower relative risk of major bleeding compared to VKA. This risk reduction was even greater when comparing apixaban to VKA among patients with eGFR 15-30 mL/min/1.73 m2, and when comparing apixaban to dabigatran and rivaroxaban among patients with eGFR 30-49 mL/min/1.73 m2., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Background and Aims: The evidence for beta-blocker therapy after myocardial infarction (MI) is randomized trials conducted more than 30 years ago, and the continued efficacy has been questioned., Design and Methods: The ongoing Danish (DANBLOCK) and Norwegian (BETAMI) randomized beta-blocker trials are joined to evaluate the effectiveness and risks of long-term beta-blocker therapy after MI. Patients with normal or mildly reduced left ventricular ejection fraction (LVEF ≥ 40%) will be randomized to open-label treatment with beta-blockers or no such therapy. The event-driven trial will randomize ∼5700 patients and continue until 950 primary endpoints have occurred. As of July 2023, 5228 patients have been randomized. Of the first 4000 patients randomized, median age was 62 years, 79% were men, 48% had a ST-segment elevation myocardial infarction (STEMI), and 84% had a normal LVEF. The primary endpoint is a composite of adjudicated recurrent MI, incident heart failure (HF), coronary revascularization, ischaemic stroke, all-cause mortality, malignant ventricular arrhythmia, or resuscitated cardiac arrest. The primary safety endpoint includes a composite of recurrent MI, HF, all-cause mortality, malignant ventricular arrhythmia, or resuscitated cardiac arrest 30 days after randomization. Secondary endpoints include each of the components of the primary endpoint, patient-reported outcomes, and other clinical outcomes linked to beta-blocker therapy. The primary analysis will be conducted according to the intention-to-treat principle using a Cox proportional hazards regression model. End of follow-up is expected in December 2024., Conclusion: The combined BETAMI-DANBLOCK trial will have the potential to affect current clinical practice for beta-blocker therapy in patients with normal or mildly reduced LVEF after MI., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Competing Interests: Conflict of interest: C.T.-P. has received grants for studies from Novo Nordisk not related to the current study. C.M.H. has received research grants from the Novo Nordisk Foundation, TrygFonden, Helsefonden, Independent Research Fund Denmark, Strategic Research Fund, Capital Region of Denmark, and Laerdal Foundation, none are related to the current study.

Objective: To examine whether patients with ANCA-associated vasculitis (AAV) have an increased risk of cardiovascular disease in the months prior to diagnosis of AAV., Methods: Using a nested case-control framework, patients with granulomatosis with polyangiitis and microscopic polyangiitis were identified through the Danish Nationwide Registries from 1996 to 2021 and matched 1:3 with age- and sex-matched controls without AAV. Each control was assigned the same index date (date of AAV diagnosis) as their corresponding case. Conditional logistic regression was used to compute adjusted hazard ratios (HRs) for major adverse cardiovascular events (MACE), ischaemic heart disease, coronary angiogram, heart failure, venous thromboembolism, atrial fibrillation, ischaemic stroke, pericarditis and ventricular arrhythmias/implantable cardioverter defibrillator implantation/cardiac arrest (VA/ICD/CA) within 12 months, 6 months, 3 months, 2 months and 1 month before index date., Results: A total of 2371 patients with AAV (median age 63 years, 53.7% male) were matched with 7113 controls. The prevalence of any cardiovascular outcome and MACE within 12 months preceding index date were 10.3% and 2.4% for AAV, compared with 3.8% [HR 3.05 (95% CI 2.48-3.75)] and 1.3% [HR 1.98 (95% CI 1.39-2.82)] of controls. The risk of cardiovascular outcomes was similarly increased in temporal proximity to the diagnosis, with the highest HR at 1 month prior to index date: any cardiovascular outcome [HR 10.73 (95% CI 7.05-16.32)] and MACE [HR 5.78 (95% CI 2.67-12.52)]. In individual analysis, a significantly higher rate was observed for all outcomes (excluding VA/ICD/CA)., Conclusions: AAV disease is associated with an increased risk of cardiovascular disease in the months preceding diagnosis, which underlines the importance of early clinical vigilance towards cardiovascular disease., (© The Author(s) 2023. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Aims: It is unclear how serial high-sensitivity troponin-I (hsTnI) concentrations affect long-term prognosis in individuals with suspected acute coronary syndrome (ACS)., Methods and Results: Subjects who underwent two hsTnI measurements (Siemens TnI Flex® Reagent) separated by 1-7 h, during a first-time hospitalization for myocardial infarction, unstable angina, observation for suspected myocardial infarction, or chest pain from 2012 through 2019, were identified through Danish national registries. Individuals were stratified per their hsTnI concentration pattern (normal, rising, persistently elevated, or falling) and the magnitude of hsTnI concentration change (<20%, >20-50%, or >50% in either direction). We calculated absolute and relative mortality risks standardized to the distributions of risk factors for the entire study population. A total of 20 609 individuals were included of whom 2.3% had died at 30 days, and an additional 4.7% had died at 365 days. The standardized risk of death was highest among persons with a persistently elevated hsTnI concentration (0-30 days: 8.0%, 31-365 days: 11.1%) and lowest among those with two normal hsTnI concentrations (0-30 days: 0.5%, 31-365 days: 2.6%). In neither case did relative hsTnI concentration changes between measurements clearly affect mortality risk. Among persons with a rising hsTnI concentration pattern, 30-day mortality was higher in subjects with a >50% rise compared with those with a less pronounced rise (2.2% vs. <0.1%)., Conclusion: Among individuals with suspected ACS, those with a persistently elevated hsTnI concentration consistently had the highest risk of death. In subjects with two normal hsTnI concentrations, mortality was very low and not affected by the magnitude of change between measurements., Competing Interests: Conflict of interest: M.P. discloses the following relationships—advisory board: AstraZeneca, Janssen-Cilag, and Novo Nordisk; grant support: Danish Cardiovascular Academy funded by the Novo Nordisk Foundation and the Danish Heart Foundation (grant number CPD5Y-2022004-HF); and speaker honorarium: AstraZeneca, Bayer, Boehringer Ingelheim, and Janssen-Cilag. M.V. has received research grant support or served on advisory boards for American Regent, Amgen, AstraZeneca, Bayer AG, Baxter Healthcare, Boehringer Ingelheim, Cytokinetics, Lexicon Pharmaceuticals, Relypsa, and Roche Diagnostics; speaker engagements with Novartis and Roche Diagnostics; and participates on clinical endpoint committees for studies sponsored by Galmed and Novartis. C.B. discloses the following relationships—speaker honorarium: Bayer. T.B.-S. discloses the following relationships—steering committee member of the Amgen-financed GALACTIC-HF trial, chief investigator and steering committee chair of the Sanofi Pasteur–financed ‘NUDGE-FLU’ trial, chief investigator and steering committee chair of the Sanofi Pasteur–financed ‘DANFLU-1’ trial, chief investigator and steering committee chair of the Sanofi Pasteur–financed ‘DANFLU-2’ trial, and steering committee member of ‘LUX-Dx TRENDS Evaluates Diagnostics Sensors in Heart Failure Patients Receiving Boston Scientific’s Investigational ICM System’ trial; advisory board: Sanofi Pasteur, Amgen, and GSK; speaker honorarium: Novartis, Sanofi Pasteur, and GSK; and research grants: GE Healthcare and Sanofi Pasteur. M.M. is supported by a grant from the Novo Nordisk Foundation (grant number NNFOC0074083) and has received lecture and advisory board fees from Novo Nordisk. C.P.M. is supported by a grant from the National Institutes of Health (K23HL167659) and has received consulting fees/honorarium from Roche Diagnostics and Abbott Laboratories. L.K. discloses the following relationships—speaker honorarium from Novo Nordisk, Novartis, AstraZeneca, Boehringer, and Bayer. N.T.O. discloses the following relationships—research funding: Abbott and Shockwave. D.L.B. discloses the following relationships—advisory board: Angiowave, Bayer, Boehringer Ingelheim, Cardax, CellProthera, Cereno Scientific, Elsevier Practice Update Cardiology, High Enroll, Janssen, Level Ex, McKinsey, Medscape Cardiology, Merck, MyoKardia, NirvaMed, Novo Nordisk, PhaseBio, PLx Pharma, and Stasys; board of directors: American Heart Association New York City, Angiowave (stock options), Bristol Myers Squibb (stock), DRS.LINQ (stock options), and High Enroll (stock); consultant: Broadview Ventures and Hims; data monitoring committees: Acesion Pharma, Assistance Publique-Hôpitaux de Paris, Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute, for the PORTICO trial, funded by St. Jude Medical, now Abbott), Boston Scientific (chair, PEITHO trial), Cleveland Clinic, Contego Medical (chair, PERFORMANCE 2), Duke Clinical Research Institute, Mayo Clinic, Mount Sinai School of Medicine (for the ENVISAGE trial, funded by Daiichi Sankyo; for the ABILITY-DM trial, funded by Concept Medical), Novartis, Population Health Research Institute, and Rutgers University (for the NIH-funded MINT Trial); honoraria: American College of Cardiology (senior associate editor, Clinical Trials and News, ACC.org; chair, ACC Accreditation Oversight Committee), Arnold and Porter law firm (work related to Sanofi/Bristol-Myers Squibb clopidogrel litigation), Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute; RE-DUAL PCI clinical trial steering committee funded by Boehringer Ingelheim; AEGIS-II executive committee funded by CSL Behring), Belvoir Publications (editor in chief, Harvard Heart Letter), Canadian Medical and Surgical Knowledge Translation Research Group (clinical trial steering committees), CSL Behring (AHA lecture), Cowen and Company, Duke Clinical Research Institute (clinical trial steering committees, including for the PRONOUNCE trial, funded by Ferring Pharmaceuticals), HMP Global (editor in chief, Journal of Invasive Cardiology), Journal of the American College of Cardiology (guest editor, associate editor), K2P (co-chair, interdisciplinary curriculum), Level Ex, Medtelligence/ReachMD (CME steering committees), MJH Life Sciences, Oakstone CME (course director, Comprehensive Review of Interventional Cardiology), Piper Sandler, Population Health Research Institute (for the COMPASS operations committee, publications committee, steering committee, and US national co-leader, funded by Bayer), WebMD (CME steering committees), and Wiley (steering committee); other: Clinical Cardiology (deputy editor); patent: Sotagliflozin (named on a patent for sotagliflozin assigned to Brigham and Women’s Hospital who assigned to Lexicon; neither I nor Brigham and Women’s Hospital receive any income from this patent); research funding: Abbott, Acesion Pharma, Afimmune, Aker Biomarine, Alnylam, Amarin, Amgen, AstraZeneca, Bayer, Beren, Boehringer Ingelheim, Boston Scientific, Bristol-Myers Squibb, Cardax, CellProthera, Cereno Scientific, Chiesi, CinCor, Cleerly, CSL Behring, Eisai, Ethicon, Faraday Pharmaceuticals, Ferring Pharmaceuticals, Forest Laboratories, Fractyl, Garmin, HLS Therapeutics, Idorsia, Ironwood, Ischemix, Janssen, Javelin, Lexicon, Lilly, Medtronic, Merck, Moderna, MyoKardia, NirvaMed, Novartis, Novo Nordisk, Otsuka, Owkin, Pfizer, PhaseBio, PLx Pharma, Recardio, Regeneron, Reid Hoffman Foundation, Roche, Sanofi, Stasys, Synaptic, The Medicines Company, Youngene, and 89Bio; royalties: Elsevier (editor, Braunwald’s Heart Disease); site co-investigator: Abbott, Biotronik, Boston Scientific, CSI, Endotronix, St. Jude Medical (now Abbott), Philips, SpectraWAVE, Svelte, and Vascular Solutions; trustee: American College of Cardiology; and unfunded research: FlowCo and Takeda. The other authors report no relevant disclosures., (© 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.)

Objectives: Osteoarticular infection (OAI) is a feared complication of Staphylococcus aureus bacteraemia (SAB) and is associated with poor outcomes. We aimed to explore risk of OAI and death following SAB in patients with and without rheumatoid arthritis (RA) and to identify risk factors for OAI in patients with RA., Methods: Danish nationwide cohort study of all patients with microbiologically verified first-time SAB between 2006-2018. We identified RA, SAB, comorbidities, and RA-related characteristics (e.g. orthopaedic implants, antirheumatic treatment) in national registries including the rheumatology registry DANBIO. We estimated cumulative incidence of OAI and death and adjusted hazard ratios (HRs, multivariate Cox regression)., Results: We identified 18 274 patients with SAB (n = 367 with RA). The 90-day cumulative incidence of OAI was 23.1%(95%CI 18.8; 27.6) for patients with RA and 12.5%(12.1; 13.0) for patients without RA (non-RA) (HR 1.93(1.54; 2.41)). For RA patients with orthopaedic implants cumulative incidence was 29.4%(22.9; 36.2) (HR 1.75(1.08; 2.85), and for current users of tumor necrosis factor inhibitors (TNFi) it was 41.9%(27.0; 56.1) (HR 2.27(1.29; 3.98) compared with non-users). All-cause 90-day mortality following SAB was similar in RA (35.4%(30.6; 40.3)) and non-RA (33.9%(33.2; 34.5), HR 1.04(0.87; 1.24))., Conclusion: Following SAB, almost one in four patients with RA contracted OAI corresponding to a doubled risk compared with non-RA. In RA, orthopaedic implants and current TNFi use were associated with approximately doubled OAI risk. One in three died within 90 days in both RA and non-RA. These findings encourage vigilance in RA patients with SAB to avoid treatment delay of OAI., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background and Aims: A rising number of countries allow physicians to treat chronic pain with medical cannabis. However, recreational cannabis use has been linked with cardiovascular side effects, necessitating investigations concerning the safety of prescribed medical cannabis., Methods: Using nationwide Danish registers, patients with chronic pain initiating first-time treatment with medical cannabis during 2018-21 were identified and matched 1:5 to corresponding control patients on age, sex, chronic pain diagnosis, and concomitant use of other pain medication. The absolute risks of first-time arrhythmia (atrial fibrillation/flutter, conduction disorders, paroxysmal tachycardias, and ventricular arrhythmias) and acute coronary syndrome were reported comparing medical cannabis use with no use., Results: Among 1.88 million patients with chronic pain (46% musculoskeletal, 11% cancer, 13% neurological, and 30% unspecified pain), 5391 patients claimed a prescription of medical cannabis [63.2% women, median age: 59 (inter-quartile range 48-70) years] and were compared with 26 941 control patients of equal sex- and age composition. Arrhythmia was observed in 42 and 107 individuals, respectively, within 180 days. Medical cannabis use was associated with an elevated risk of new-onset arrhythmia {180-day absolute risk: 0.8% [95% confidence interval (CI) 0.6%-1.1%]} compared with no use [180-day absolute risk: 0.4% (95% CI 0.3%-0.5%)]: a risk ratio of 2.07 (95% CI 1.34-2.80) and a 1-year risk ratio of 1.36 (95% CI 1.00-1.73). No significant association was found for acute coronary syndrome [180-day risk ratio: 1.20 (95% CI 0.35-2.04)]., Conclusions: In patients with chronic pain, the use of prescribed medical cannabis was associated with an elevated risk of new-onset arrhythmia compared with no use-most pronounced in the 180 days following the initiation of treatment., (© The Author(s) 2024. 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.)

Background and Aims: Aspirin is considered mandatory after myocardial infarction (MI). However, its long-term efficacy has been questioned. This study investigated the effectiveness of long-term aspirin after MI., Methods: Patients ≥ 40 years with MI from 2004-2017 who were adherent to aspirin one year after MI were included from Danish nationwide registries. At 2, 4, 6, and 8 years after MI, continued adherence to aspirin was evaluated. Absolute and relative risks of MI, stroke, or death at 2 years from each timepoint were calculated using multivariable logistic regression analysis with average treatment effect modeling standardized for age, sex, and comorbidities. Subgroup analyses were stratified by sex and age > and ≤ 65 years., Results: Among 40 114 individuals included, the risk of the composite endpoint was significantly higher for nonadherent patients at all timepoints. The absolute risk was highest at 2-4 years after MI for both adherent (8.34%, 95% confidence interval [CI]: 8.05-8.64%) and nonadherent patients (10.72%, 95% CI: 9.78-11.66%). The relative risk associated with nonadherence decreased from 4 years after index-MI and onwards: 1.41 (95% CI: 1.27-1.55) at 4-6 years and 1.21 (95% CI: 1.06-1.36) at 8-10 years (Ptrend = 0.056). Aspirin nonadherence in women and individuals > 65 years was not associated with increased risk. Pinteraction at each of the timepoints: Age-<0.001, <0.001, 0.002, 0.51; Sex - 0.25, 0.02, 0.02, 0.82., Conclusion: Nonadherence to long-term aspirin was associated with increased risk of MI, stroke, or death, but not in women or individuals > 65 years. The risk decreased from 4 years after MI with near statistical significance., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Introduction: Older adults are susceptible to anticholinergic effects. Dysphagia and pneumonia are associated with anticholinergic usage, though a definitive causative relationship has not been established. There is no effective way to predict the prognosis of older adults with pneumonia; therefore, this study investigates the predictive value of anticholinergic burden., Methods: Patients aged 65 years and above admitted for community-acquired pneumonia from 2011 to 2018 in Denmark were included through Danish registries. We calculated anticholinergic drug exposure using the CRIDECO Anticholinergic Load Scale (CALS). The primary outcome was in-hospital mortality, and other outcomes included intensive care unit admission, ventilator usage, length of stay, 30-day/90-day/1-year mortality, institutionalisation, home care utilisation and readmission., Results: 186,735 patients were included in the in-hospital outcome analyses, 165,181 in the readmission analysis, 150,791 in the institutionalisation analysis, and 95,197 and 73,461 patients in the home care analysis at follow-up. Higher CALS score was associated with higher in-hospital mortality, with a mean risk increasing from 9.9% (CALS 0) to 16.4% (CALS >10), though the risk plateaued above a CALS score of 8. A higher CALS score was also associated with greater mortality after discharge, more home health care, more institutionalizations and higher readmission rates., Conclusions: High anticholinergic burden levels were associated with poor patient outcomes including short-/long-term mortality, dependence and readmission. It may be useful to calculate the CALS score on admission of older patients with pneumonia to predict their prognosis. This also highlights the importance of avoiding the use of drugs with a high anticholinergic burden in older patients., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Geriatrics Society. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Linezolid in combination with rifampicin has been used in treatment of infective endocarditis especially for patients infected with staphylococci., Objectives: Because rifampicin has been reported to reduce the plasma concentration of linezolid, the present study aimed to characterize the population pharmacokinetics of linezolid for the purpose of quantifying an effect of rifampicin cotreatment. In addition, the possibility of compensation by dosage adjustments was evaluated., Patients and Methods: Pharmacokinetic measurements were performed in 62 patients treated with linezolid for left-sided infective endocarditis in the Partial Oral Endocarditis Treatment (POET) trial. Fifteen patients were cotreated with rifampicin. A total of 437 linezolid plasma concentrations were obtained. The pharmacokinetic data were adequately described by a one-compartment model with first-order absorption and first-order elimination., Results: We demonstrated a substantial increase of linezolid clearance by 150% (95% CI: 78%-251%), when combined with rifampicin. The final model was evaluated by goodness-of-fit plots showing an acceptable fit, and a visual predictive check validated the model. Model-based dosing simulations showed that rifampicin cotreatment decreased the PTA of linezolid from 94.3% to 34.9% and from 52.7% to 3.5% for MICs of 2 mg/L and 4 mg/L, respectively., Conclusions: A substantial interaction between linezolid and rifampicin was detected in patients with infective endocarditis, and the interaction was stronger than previously reported. Model-based simulations showed that increasing the linezolid dose might compensate without increasing the risk of adverse effects to the same degree., (© The Author(s) 2023. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Little data exist on the risk and outcomes of out-of-hospital cardiac arrest (OHCA) in people with HIV (PWH). We aimed to describe OHCA in PWH as compared with the general population in terms of incidence, characteristics, and survival., Methods: This nationwide study assessed all individuals aged 18-85 years between 2001 and 2019 in Denmark. The cumulative incidence of OHCA was computed using cause-specific Cox models accounting for competing risk of death., Results: Among 6 565 309 individuals, 6 925 (median age: 36; interquartile range [IQR]: 28-44 y; 74% males) were infected at some point with HIV. The incidence of OHCA was 149 (95% CI: 123-180)/100 000 person-years in PWH versus 64 (95% CI: 64-65)/100 000 person-years in people without HIV (P < .001). Age at the time of cardiac arrest was 52 (IQR: 44-61) years in PWH versus 69 (IQR: 59-77) years in individuals without HIV (P < .001). In a multivariable model adjusted for age, sex, hypertension, diabetes, heart failure, ischemic heart disease, atrial fibrillation, chronic obstructive pulmonary disease, cancer, and renal failure, PWH had a 2-fold higher risk of OHCA (hazard ratio: 2.84; 95% CI: 2.36-3.43; P < .001). Thirty-day mortality (89% vs 88%; P = .80) was comparable to individuals without HIV., Conclusions: HIV is an independent risk factor for OHCA, and those who experience OHCA with HIV are much younger than those without HIV. Almost 90% of PWH died 1 month after OHCA. Further research should strive to find out how to reduce OHCA occurrence in this population., Competing Interests: Potential conflicts of interest. C. T.-P. reports a grant for a randomized study from Bayer and a grant for epidemiological study from Novo Nordisk. P. E. W. reports an institutional travel grant from Medtronic. J. T.-H. reports project support from the Novo Nordisk Foundation (Tandem Programme no. 31634) and from the John and Birth Meyer Foundation and consulting fees from Johnson and Johnson, Microport, Cytokinetics, and Leo Pharma (paid to the author). C. J. H. reports travel grant support from Medtronic outside the scope of this work. T. B. reports unrestricted institutional grants from Novo Nordisk Foundation, Simonsen Foundation, Lundbeck Foundation, Kai Foundation, Erik and Susanna Olesen's Charitable Fund, GSK, and Pfizer; grants or contracts from Boehringer Ingelheim, MSD, Pentabase, Roche, Novartis, Kancera AB, Janssen, and AstraZeneca; consulting fees from GSK and Pfizer; honoraria for lectures from GSK, Pfizer, Gilead Sciences, Boehringer Ingelheim, Abbvie, and AstraZeneca; advisory board participation with GSK, Gilead Sciences, MSD, Pentabase, Janssen, and AstraZeneca; and receipt of donated trial medication (baricitinib) from Eli Lilly. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Aim: Methylphenidate, a sympathomimetic drug prescribed to treat attention-deficit/hyperactivity disorder (ADHD), is associated with cardiovascular events, but few studies have explored the risk of out-of-hospital cardiac arrest (OHCA). We investigated whether methylphenidate use is associated with OHCA in the general population., Methods and Results: Using Danish nationwide registries, we conducted a nested case-control study with OHCA cases of presumed cardiac causes and age/sex/OHCA-date-matched non-OHCA controls from the general population. Conditional logistic regression models with adjustments for well-known risk factors of OHCA were employed to estimate the odds ratio (OR) of OHCA by comparing methylphenidate use with no use of methylphenidate.The study population consisted of 46 578 OHCA cases [median: 72 years (interquartile range: 62-81), 68.8% men] and 232 890 matched controls. Methylphenidate was used by 80 cases and 166 controls, and was associated with an increased OR of OHCA compared with non-users {OR: 1.78 [95% confidence interval (CI): 1.32-2.40]}. The OR was highest in recent starters (OR≤180 days: 2.59, 95% CI: 1.28-5.23). The OR of OHCA associated with methylphenidate use did not vary significantly by age (P-value interaction: 0.37), sex (P-value interaction: 0.94), and pre-existing cardiovascular disease (P-value interaction: 0.27). Furthermore, the ORs remained elevated when we repeated the analyses in individuals without registered hospital-based ADHD (OR: 1.85, 95% CI: 1.34-2.55), without severe psychiatric disorders (OR: 1.98, 95% CI: 1.46-2.67), without depression (OR: 1.93, 95% CI: 1.40-2.65), or in non-users of QT-prolonging drugs (OR: 1.79, 95% CI: 1.27-2.54)., Conclusion: Methylphenidate use is associated with an increased risk of OHCA in the general population. This increased risk applies to both sexes and is independent of age and the presence of cardiovascular disease., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Aims: To characterize and follow patients with ST-segment elevation myocardial infarction (STEMI) at high bleeding risk (HBR) according to the predicting bleeding complications in patients undergoing stent implantation and subsequent dual antiplatelet therapy (PRECISE-DAPT) score, and to examine the use of P2Y12 inhibitors and the subsequent risk of major adverse cardiovascular events (MACE) and bleeding., Methods and Results: This single-centre cohort study included 6179 consecutive STEMI patients who underwent percutaneous coronary intervention (PCI) at Copenhagen University Hospital, Rigshospitalet, between 2009 and 2016. Individual linkage to nationwide registries was conducted to obtain information on diagnoses, claimed drugs, and vital status. Of the 5532 (89.5%) patients with available PRECISE-DAPT scores, 33.0% were at HBR and more often elderly and female with more comorbidities than non-HBR patients. One-year cumulative incidence rates per 100 person-years were 8.7 and 2.1 for major bleeding and 36.8 and 8.3 for MACE in HBR and non-HBR patients, respectively. Among the 4749 (85.8%) patients who survived and collected a P2Y12 inhibitor ≤7 days from discharge, 68.2% of HBR patients were treated with ticagrelor or prasugrel and 31.8% with clopidogrel, while 18.2% non-HBR patients were treated with clopidogrel. Adherence was high for all (>75% days coverage). The risk of MACE was lower in ticagrelor- and prasugrel-treated patients than in clopidogrel-treated patients without differences in major bleeding., Conclusion: One-third of PCI-treated all-comer patients with STEMI were at HBR according to the PRECISE-DAPT score and were more often treated with potent P2Y12 inhibitors instead of clopidogrel. Thus, ischaemic risk may be weighted over bleeding risk in STEMI patients at HBR., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Background: Epidemiologic assessments of anti-glomerular basement membrane (GBM) disease have been challenging due to its rare occurrence. We examined changes in the incidence and outcomes from 1998 to 2018 using nationwide healthcare registries., Methods: All patients with incident anti-GBM disease were identified using the International Classification of Diseases, 10th Revision code DM31.0A. Controls were matched 4:1 on birthyear and sex using exposure density sampling. Log link regression adjusted for time, age and sex was applied to model survival., Results: We identified 97 patients with incident anti-GBM disease, corresponding to an incidence of 0.91 cases/million/year [standard deviation (SD) 0.6]. The incidence increased over time [1998-2004: 0.50 (SD 0.2), 2005-2011: 0.80 (SD 0.4), 2012-2018: 1.4 (SD 0.5); P  = .02] and with age [0.76 (SD 0.4), 1.5 (SD 1.04) and 4.9 (SD 2.6) for patients <45, 45-75 and >75 years]. The median age was 56 years (interquartile range 46) and 51.6% were female. Dialysis was required in 58.4%, 61.9% and 62.9% of patients at day 30, 180 and 360, respectively. The 1-year kidney survival probability was 0.38 (SD 0.05) and exhibited time-dependent changes [1998-2004: 0.47 (SD 0.13), 2005-2011: 0.16 (SD 0.07), 2012-2018: 0.46 (SD 0.07); P  = .035]. The 5-year mortality was 26.8% and mortality remained stable over time ( P  = .228). The risk of death was greater than that of the matched background population {absolute risk ratio [ARR] 5.27 [confidence interval (CI) 2.45-11.3], P  < .001}, however, it was comparable to that of patients with anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV) requiring renal dialysis at presentation [ARR 0.82 (CI 0.48-1.41), P  = .50]., Conclusion: The incidence of anti-GBM disease increased over time, possibly related to temporal demographic changes. Mortality remained high and was comparable with an age- and sex-matched cohort of dialysis-dependent AAV patients., Competing Interests: None of the authors have any conflicts of interests., (© The Author(s) 2023. Published by Oxford University Press on behalf of the ERA.)

Aims: We studied the effect of discontinuing beta-blockers following myocardial infarction in comparison to continuous beta-blocker use in optimally treated, stable patients without heart failure., Methods and Results: Using nationwide registers, we identified first-time myocardial infarction patients treated with beta-blockers following percutaneous coronary intervention or coronary angiography. The analysis was based on landmarks selected as 1, 2, 3, 4, and 5 years after the first redeemed beta-blocker prescription date. The outcomes included all-cause death, cardiovascular death, recurrent myocardial infarction, and a composite outcome of cardiovascular events and procedures. We used logistic regression and reported standardized absolute 5-year risks and risk differences at each landmark year. Among 21 220 first-time myocardial infarction patients, beta-blocker discontinuation was not associated with an increased risk of all-cause death, cardiovascular death, or recurrent myocardial infarction compared with patients continuing beta-blockers (landmark year 5; absolute risk difference [95% confidence interval]), correspondingly; -4.19% [-8.95%; 0.57%], -1.18% [-4.11%; 1.75%], and -0.37% [-4.56%; 3.82%]). Further, beta-blocker discontinuation within 2 years after myocardial infarction was associated with an increased risk of the composite outcome (landmark year 2; absolute risk [95% confidence interval] 19.87% [17.29%; 22.46%]) compared with continued beta-blocker use (landmark year 2; absolute risk [95% confidence interval] 17.10% [16.34%; 17.87%]), which yielded an absolute risk difference [95% confidence interval] at -2.8% [-5.4%; -0.1%], however, there was no risk difference associated with discontinuation hereafter., Conclusion: Discontinuation of beta-blockers 1 year or later after a myocardial infarction without heart failure was not associated with increased serious adverse events., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Aims: Guidelines do not differentiate between the available assays of cardiac troponin (cTn). We compared the prognostic and predictive ability of cTn assays., Methods and Results: This was a nationwide cohort study of patients with acute coronary syndrome (ACS) and ≥ 2 cTn measurements of one of four assays: Roche high-sensitivity cTnT (hs-cTnT), Abbott high sensitivity cTnI (hs-cTnI), Siemens Vista cTnI, and Siemens cTnI Ultra. Data were collected from Danish registries from 2009-18. Peak cTn concentration normalized to the 99th percentile was used. Outcomes were myocardial infarction (MI) during admission, one-year all-cause-, cardiovascular-, and non-cardiovascular mortality. Receiver operating characteristics and logistic regression calculating odds ratios (OR) were used. A total of 90 705 patients were included, of which 20 550 (23%) had MI. Siemens Vista cTnI was the strongest predictor of MI, Area under the curve (auc) 0.93 (95% CI 0.93-0.93). In 1 year 9012 (9.9%) of patients had died. An inverted U-shape relationship was observed between concentration of cTn and all-cause mortality. Hs-cTnT OR 21.3 (95% CI 18.4-24.8) at 2-5 times the 99th percentile and 12.1 (95% CI 10.3-14.1) for concentrations >100 times the 99th percentile. The inverted U-shape relationship was only present for non-cardiovascular mortality. The strongest predictor of cardiovascular mortality was hs-cTnT, OR 11.3 (95% CI 6.4-21.8) at 1-2 times the 99th percentile and 88.8 (95% CI 53.2-163.0) for concentrations >100 times the 99th percentile., Conclusion: Siemens Vista cTnI was the strongest predictor of MI and hs-cTnT was the strongest predictor of mortality. An inverted U-shape relationship was observed between cTn concentration and non-cardiovascular mortality., (© The Author(s) 2022. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Aims: The risk, characteristics, and outcome of out-of-hospital cardiac arrest (OHCA) in patients with congenital heart disease (CHD) remain scarcely investigated., Methods and Results: An epidemiological registry-based study was conducted. Using time-dependent Cox regression models fitted with a nested case-control design, hazard ratios (HRs) with 95% confidence intervals of OHCA of presumed cardiac cause (2001-19) associated with simple, moderate, and severe CHD were calculated. Moreover, using multiple logistic regression, we investigated the association between pre-hospital OHCA characteristics and 30-day survival and compared 30-day survival in OHCA patients with and without CHD. Overall, 43 967 cases (105 with simple, 144 with moderate, and 53 with severe CHD) and 219 772 controls (median age 72 years, 68.2% male) were identified. Any type of CHD was found to be associated with higher rates of OHCA compared with the background population [simple CHD: HR 1.37 (1.08-1.70); moderate CHD: HR 1.64 (1.36-1.99); and severe CHD: HR 4.36 (3.01-6.30)]. Pre-hospital cardiopulmonary resuscitation and defibrillation were both associated with improved 30-day survival in patients with CHD, regardless of CHD severity. Among patients with OHCA, simple, moderate, and severe CHD had a similar likelihood of 30-day survival compared with no CHD [odds ratio 0.95 (0.53-1.69), 0.70 (0.43-1.14), and 0.68 (0.33-1.57), respectively]., Conclusion: A higher risk of OHCA was found throughout the spectrum of CHD. Patients with and without CHD showed the same 30-day survival, which relies on the pre-hospital chain of survival, namely cardiopulmonary resuscitation and defibrillation., (© 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.)

Aims: Aspirin therapy for primary prevention of cardiovascular disease (CVD) is controversial, and guideline recommendations have changed throughout the last decades. We report temporal trends in primary prevention aspirin use among persons with and without diabetes and describe characteristics of incident aspirin users., Methods and Results: Using Danish nationwide registries, we identified incident and prevalent aspirin users in a population of subjects ≥40 years without CVD eligible for primary preventive aspirin therapy from 2000 through 2020. Temporal trends in aspirin users with and without diabetes were assessed, as were CVD risk factors among incident users. A total of 522 680 individuals started aspirin therapy during the study period. The number of incident users peaked in 2002 (39 803 individuals, 1.78% of the eligible population) and was the lowest in 2019 (11 898 individuals, 0.49%), with similar trends for subjects with and without diabetes. The percentage of incident users with no CVD risk factors [diabetes, hypertension, hypercholesterolemia, or chronic obstructive pulmonary disease (a proxy for smoking)] decreased from 53.9% in 2000 to 30.9% in 2020. The temporal trends in prevalent aspirin users followed a unimodal curve, peaked at 7.7% in 2008, and was 3.3% in 2020. For subjects with diabetes, the peak was observed in 2009 at 38.5% decreasing to 17.1% in 2020., Conclusion: Aspirin therapy for primary prevention of CVD has decreased over the last two decades. However, the drug remained used in individuals with and without diabetes, and a large proportion of individuals started on aspirin therapy had no CVD risk factors., Competing Interests: Conflict of interest: M.P. discloses the following relationships not related to the content of the manuscript—Advisory Board: AstraZeneca, Janssen-Cilag; Grant Support: Danish Cardiovascular Academy funded by the Novo Nordisk Foundation and the Danish Heart Foundation (grant number: CPD5Y-2022004-HF); Speaker Honorarium: AstraZeneca, Bayer, Boehringer Ingelheim, Janssen-Cilag., (© 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.)

Aims: Describe and compare incidences across age groups of rehospitalization, repeated aortic surgery, and death in patients who survived surgery and hospitalization for type A aortic dissection., Methods and Results: From Danish nationwide registries, we identified patients hospitalized with Stanford type A aortic dissections (2006-2018). Survivors of hospitalization and surgery on the ascending aorta and/or aortic arch comprised the study population (n = 606, 36 (38.9%) <60 years old (group I), 194 (32.0%) 60-69 years old (group II), and 176 (29.1%) >69 years old (group III)). During the first year, 62.5% were re-hospitalized and 1.4% underwent repeated aortic surgery with no significant differences across age groups (P = 0.68 and P = 0.39, respectively). Further, 5.9% died (group I: 3.0%, group II: 8.3%, group III: 7.4%, P = 0.04). After 10 years, 8.0% had undergone repeated aortic surgery (group I: 11.5%, group II: 8.5%, group III: 1.6%, P = 0.04) and 10.2% (group I), 17.0% (group II), and 22.2% (group III) had died (P = 0.01). Using multivariable Cox regression analysis, we described long-term outcomes comparing age groups. No age differences were found in one-year outcomes, while age > 69 years compared with age < 60 years was associated with a lower rate of repeated aortic surgery [hazard ratio 0.17, 95% confidence interval (CI) 0.04-0.78] and a higher rate of all-cause mortality (hazard ratio 2.44, 95% CI 1.37-4.34) in the 10-year analyses., Conclusion: Rehospitalisations in the first year after discharge were common in all age groups, but survival was high. Repeated aortic surgery was significantly more common among younger than older patients., (© The Author(s) 2022. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Background: Influenza vaccination protects against morbidity and mortality in patients with cardiovascular disease (CVD). We aimed to describe influenza vaccine uptake in patients with CVD in a universal-access healthcare system., Methods: Using nationwide Danish registries, we included all patients with prevalent CVD, defined as heart failure (HF), atrial fibrillation (AF), ischemic heart disease (IHD), or stroke during three consecutive influenza seasons (October-December 2017-2019). The outcome was relative frequency of influenza vaccination across strata of patient characteristics., Results: There was an average of 397 346 patients with CVD yearly during 2017-2019. Vaccine uptake was 45.6% for the whole population and ranged from 55.0% in AF to 61.8% in HF among patients aged ≥65 years. Among patients aged <65 years, uptake was 32.6% in HF, 19.0% in AF, 21.1% in IHD, and 18.3% in stroke. There was a lower uptake with decreasing age: 21.6% in HF, 5.5% in AF, 7.4% in IHD, and 6.3% in stroke among males aged <45 years, as opposed to 25.5% in HF, 11.5% in AF, 13.8% in IHD, and 12.1% in stroke for males aged 45-54 years. In the further stratified analyses, uptake ranged from a low of 2.5% for males <45 years with AF who were not vaccinated the previous season to a high of 87.0% for females ≥75 years with IHD who were vaccinated the previous season., Conclusion: Seasonal influenza vaccine uptake is suboptimal among patients with CVD, even in a universal-access healthcare system with free-of-charge vaccinations. Vaccine uptake was particularly low among young patients., (© The Author(s) 2022. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Aims: Sodium-glucose cotransporter-2 inhibitors (SGLT-2is) are antidiabetic drugs that have beneficial direct effects on the myocardium by impacting cardiac ion channels and exchangers that control cardiac electrophysiology. We investigated the relationship between SGLT-2is in comparison to glucagon-like peptide-1 receptor agonists (GLP-1as) and out-of-hospital cardiac arrest (OHCA) in individuals with type 2 diabetes., Methods: Using data from Danish registries, we conducted a nationwide nested case-control study in a cohort of individuals with type 2 diabetes between 2013 and 2019. Cases were defined as OHCA victims from presumed cardiac causes and each case was randomly matched with five controls without OHCA based on age, sex, and index-date (OHCA date). Conditional logistic regression models were used to estimate the adjusted odds ratios (ORs) with 95% confidence interval (95% CI) of OHCA comparing SGLT-2i use with GLP-1as (reference)., Results: The study population consisted of 3618 OHCA cases and 18 090 matched controls. SGLT-2i was used by 91 cases and 593 controls, and was associated with reduced odds of OHCA compared with use of GLP-1a after controlling for the relevant confounders (adjusted OR 0.76 [95% CI:0.58-0.99]). The adjusted OR of OHCA associated with SGLT-2i use did not vary significantly by sex (P-value interaction: 0.461), pre-existing cardiac disease (P-value interaction: 0.762), heart failure (P-value interaction: 0.891), diabetes duration (P-value interaction: 0.101), and chronic kidney disease (P-value interaction: 0.894)., Conclusion: Use of SGLT-2i is associated with a reduced risk of OHCA compared with use of GLP-1a in type 2 diabetes., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Aims: To date, potential differences in outcomes for immigrants and non-immigrants with a cardiac resynchronization therapy (CRT), in a European setting, remain underutilized and unknown. Hence, we examined the efficacy of CRT measured by heart failure (HF)-related hospitalizations and all-cause mortality among immigrants and non-immigrants., Methods and Results: All immigrants and non-immigrants who underwent first-time CRT implantation in Denmark (2000-2017) were identified from nationwide registries and followed for up to 5 years. Differences in HF related hospitalizations and all-cause mortality were evaluated by Cox regression analyses. From 2000 to 2017, 369 of 10 741 (3.4%) immigrants compared with 7855 of 223 509 (3.5%) non-immigrants with a HF diagnosis underwent CRT implantation. The origins of the immigrants were Europe (61.2%), Middle East (20.1%), Asia-Pacific (11.9%), Africa (3.5%), and America (3.3%). We found similar high uptake of HF guideline-directed pharmacotherapy before and after CRT and a consistent reduction in HF-related hospitalizations the year before vs. the year after CRT (61% vs. 39% for immigrants and 57% vs. 35% for non-immigrants). No overall difference in 5-year mortality among immigrants and non-immigrants was seen after CRT [24.1% and 25.8%, respectively, P-value = 0.50, hazard ratio (HR) = 1.2, 95% confidence interval (CI): 0.8-1.7]. However, immigrants of Middle Eastern origin had a higher mortality rate (HR = 2.2, 95% CI: 1.2-4.1) compared with non-immigrants. Cardiovascular causes were responsible for the majority of deaths irrespective of immigration status (56.7% and 63.9%, respectively)., Conclusion: No overall differences in efficacy of CRT in improving outcomes between immigrants and non-immigrants were identified. Although numbers were low, a higher mortality rate among immigrants of Middle Eastern origin was identified compared with non-immigrants., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Aims: Reduced psychological health is associated with adverse patient outcomes and higher mortality. We aimed to examine if a Brugada syndrome (BrS) diagnosis and symptomatic disease presentation were associated with an increased risk of new-onset depression or anxiety and all-cause mortality., Methods and Results: All Danish patients diagnosed with BrS (2006-2018) with no history of psychiatric disease and available for ≥6 months follow-up were identified using nationwide registries and followed for up to 5 years after diagnosis. The development of clinical depression or anxiety was evaluated using the prescription of medication and diagnosis codes. Factors associated with developing new-onset depression or anxiety were determined using a multivariate Cox proportional hazards regression model. Disease manifestation was categorized as symptomatic (aborted cardiac arrest, ventricular tachycardia, or syncope) or asymptomatic/unspecified at diagnosis. A total of 223 patients with BrS and no history of psychiatric disease were identified (72.6% male, median age at diagnosis 46 years, 45.3% symptomatic). Of these, 15.7% (35/223) developed new-onset depression or anxiety after BrS diagnosis (median follow-up 5.0 years). A greater proportion of symptomatic patients developed new-onset depression or anxiety compared with asymptomatic patients [21/101 (20.8%) and 14/122 (11.5%), respectively, P = 0.08]. Symptomatic disease presentation (HR 3.43, 1.46-8.05) and older age (lower vs. upper tertile: HR 4.41, 1.42-13.63) were significantly associated with new-onset depression or anxiety. All-cause mortality in this group of patients treated according to guidelines was low (n = 4, 1.8%); however, 3/4 developed depression or anxiety before death., Conclusion: Approximately, one-sixth of patients with BrS developed new-onset depression or anxiety following a diagnosis of BrS. Symptomatic BrS disease manifestation was significantly associated with new-onset depression or anxiety., Competing Interests: Conflict of interest: None declared., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Aims: While clinical trials have suggested that a high ventricular rate is associated with increased risk of heart failure (HF) and mortality, all-comers studies are warranted., Objective: To assess 1-year risk of new-onset diagnosed HF and all-cause mortality among rate-control treated patients presenting with atrial fibrillation (AF) on an electrocardiogram (ECG) according to ventricular rate., Methods and Results: ECGs recorded at the Copenhagen General Practitioners Laboratory (2001-15) were used to identify patients with AF. Multivariate Cox proportional hazard regression models were used to compare risk of new-onset HF and all-cause mortality after first ECG presenting with AF according to ventricular rate on ECG [<60, 60-79, 80-99, and 100-110, > 110 beats per minute (bpm)]. We identified 7408 patients in treatment with rate control drugs at time of first ECG presenting with AF [median age 78 years (Q1,Q3 = 70-85 years)], 45.8% male, median ventricular rate 83 bpm, (Q1,Q3 = 71-101 bpm)]. During 1-year follow-up, 666 (9.0%) of all patients with AF developed HF and 858 (11.6%) died. Patients with AF ventricular rates 100-110 bpm and >110 bpm had a hazard ratio (HR) of 1.46 (CI: 1.10-1.95) and 2.41 (CI: 1.94-3.00) respectively for new-onset HF, compared with 60-79 bpm. Similarly, patients with AF ventricular rates 100-110 bpm and >110 bpm had a HR of 1.44 (CI: 1.13-1.82) and 1.34 (CI: 1.08-1.65) respectively for all-cause mortality, compared with 60-79 bpm., Conclusions: Ventricular rates ≥100 bpm among patients presenting with AF on ECG in treatment with rate control drugs were associated with greater risk of both new-onset HF and all-cause mortality., Competing Interests: Conflict of interest: Lucas Malta Westergaard: none, Amna Alhakak: none, Rasmus Rørth: none, Emil L. Fosbøl: none, and Søren L. Kristensen: speaker fee from Astra Zeneca. Advisory board at Bayer, Jesper H. Svendsen: research grant, payment to institution, and speaker fee from Medtronic. Advisory board at Medtronic, Claus Graff: none, Jonas B. Nielsen: is employed by Regeneron Pharmaceuticals Inc., New York, unrelated to this work; Gunnar H. Gislason: research grants from Boerhinger Ingelheim, Bristol-Myers Squibb, and Pfizer; Lars Køber: serves as a consultant for Boehringer Ingelheim and has received other support from AstraZeneca, Novartis, and Novo Nordisk; and Christian Torp-Pedersen: grant for randomized study from Bayer. Grant for epidemiological study from Novo Nordisk; Christina J-Y Lee: none; and Peter E. Weeke: none., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Background: Employment is important for physical and mental health and self-esteem and provides financial independence. However, little is known on the prognostic value of employment status prior to admission with acute myocardial infarction (MI)., Methods and Results: Using Danish nationwide registries, all patients between 18 and 60 years with a first-time MI admission (2010-2018) and alive at discharge were included. Rates of all-cause mortality and recurrent MI according to workforce attachment at the time of the event was compared using multivariable Cox regression. Of the 16 060 patients included in the study, 3520 (21.9%) patients were not part of the workforce. Patients who were not part of the workforce were older (52 vs. 51 years), less often men (63% vs. 77%), less likely to have higher education, more often living alone (47% vs. 29%), and more often had comorbidities, including heart failure, atrial fibrillation, hypertension, diabetes, chronic kidney disease, and chronic obstructive pulmonary disease. The absolute 5-year risk of death was 3.3% and 12.8% in the workforce and non-workforce group, respectively. The corresponding rates of recurrent MI were 7.5% and 10.9%, respectively. In adjusted analyses, not being part of the workforce was associated with a significantly higher rate of all-cause mortality [HR: 2.39 (95% CI: 2.01-2.83)] and recurrent MI [1.36 (1.18-1.57)]., Conclusion: Among patients of working age who were admitted with MI and alive at discharge, not being part of the workforce was associated with a higher long-term rate of all-cause mortality and recurrent MI., Competing Interests: Conflict of interest: J.H.B.: Advisory board honoraria from Bayer; consultant honoraria from Novartis and AstraZeneca; travel grants from AstraZeneca; C.T.-P.: Grants for studies from Bayer and Novo Nordisk; L.K.: Speakers honorarium from Novo, Novartis, AstraZeneca and Boehringer; E.L.F.: Independent research grant from novo nordisk foundation., (© 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.)

Aims: Cancer and heart failure (HF) share risk factors, pathophysiological mechanisms, and possibly genetics. Improved HF survival may increase the risk of cancer due to a competing risk. Whether the incidence of cancer has increased over time in patients with HF as survival has improved is unclear. Therefore, temporal trends of new onset cancer in HF patients between 1997 and 2016 were investigated., Methods and Results: Using Danish nationwide registers, 103 711 individuals alive, free of cancer, and aged 30-80 years 1 year after HF diagnosis (index date) were included between 1 January 1997 and 31 December 2016. A five-year incidence rate of cancer for each year after index date was calculated. The median age and proportion of women at the index date decreased with advancing calendar time [1997-2001: 70.3 interquartile range (Q1-Q3 62.5-75.7), 60.9% men; 2012-16: 67.6 (59.2-73.8), 67.5% men]. The five-year incidence rate of cancer was 20.9 and 20.2 per 1,000 person-years in 1997 and 2016, respectively. In a multivariable Cox regression model, the hazard rates between index years 1997 (reference) and 2016 were not significantly different [hazard ratio 1.09 (0.97-1.23)]. The five-year absolute risk of cancer did not change with advancing calendar year, going from 9.0% (1997-2001) to 9.0% (2012-16). Five-year cumulative incidence of survival for HF patients increased with advancing calendar year, going from 55.9% (1997-2001) to 74.3% (2012-2016)., Conclusion: Although cancer rates during 1997-2016 have remained stable within 1-6 years after the HF diagnosis, long-term survival following a HF diagnosis has increased significantly., Competing Interests: Conflict of interest: C.H.G. reports personal fees from lectures honorarium from Astra Zeneca unrelated to the work in question; C.T.-P. reports grants from Bayer and Novo Nordisk unrelated to the work in question; J.V.M. reports grants from Abbott, Alkem Metabolics, Eris Lifesciences, Hikma, Lupin, Sun Pharmaceuticals, Medscape/Heart.Org, ProAdWise Communications, Radcliffe Cardiology, Servier, the Corpus unrelated to the work in question; N.N.L. reports grants from Roche Diagnostics, Boehringer Ingelheim, AstraZeneca, NIHR and British Heart Foundation. Further, reports lecturer fees from Roche, Pfizer, and Novartis and consulting fees from AstraZeneca. All unrelated to the work in question; L.K. reports personal fees from speakers honorarium from Novo Nordisk, Novartis, AstraZeneca and Boehringer Ingelheim outside the submitted work; M.S. reports personal fees from lectures honorarium from Novo Nordisk, Novartis, AstraZeneca, and Boehringer Ingelheim outside the submitted work., (© 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.)

Aims: Emerging data show that complete revascularization (CR) reduces cardiovascular death and recurrent myocardial infarction in ST-segment elevation myocardial infarction (STEMI). However, the influence of revascularization status on development of arrhythmia in the long-term post-STEMI phase is poorly described. We hypothesized that incomplete revascularization (ICR) compared with CR in STEMI is associated with an increased long-term risk of new-onset arrhythmia., Methods and Results: Patients with STEMI treated with primary percutaneous coronary intervention (PPCI) at Copenhagen University Hospital, Rigshospitalet, Denmark, with CR or ICR were identified via the Eastern Danish Heart registry from 2009 to 2016. Using unique Danish administrative registries, the outcomes were assessed. The primary outcome was new-onset arrhythmia defined as a composite of atrial fibrillation/flutter (AF), sinoatrial block, advanced second- or third-degree atrioventricular block, ventricular tachycardia/fibrillation (VT), or cardiac arrest (CA), with presentation >7 days post-PPCI. Secondary outcomes were the components of the primary outcome and all-cause mortality. A total of 5103 patients (median age: 62.0 years; 76% men) were included, of whom 4009 (79%) and 1094 (21%) patients underwent CR and ICR, respectively. Compared with CR, ICR was associated with a higher risk of new-onset arrhythmia [hazard ratio (HR), 1.33; 95% confidence interval (CI), 1.07-1.66; P = 0.01], AF (HR, 1.29; 95% CI, 1.00-1.66; P = 0.05), a combined outcome of VT and CA (HR, 1.77; 95% CI, 1.10-2.84; P = 0.02) and all-cause mortality (HR, 1.27; 95% CI, 1.05-1.53; P = 0.01). All HRs adjusted., Conclusion: Among patients with STEMI, ICR was associated with an increased long-term risk of new-onset arrhythmia and all-cause mortality compared with CR., Competing Interests: Conflict of interest: C.T.-P. reports research grants from Novo Nordisk and Bayer. L.K. reports speakers’ fees from AstraZeneca, Novo Nordisk, Novartis, and Boehringer. T.E. reports speakers fee from Abbott. C.J. reports honoraria from Biotronik Inc. and speakers fee from Abbott. J.H.B. reports advisory board honoraria from Bayer, outside the submitted work. The other authors have no financial conflicts of interest to declare., (© The Author(s) 2022. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Aims: Limited data exist to describe the prognostic impact of atrial fibrillation (AF) and oral anticoagulation on patients with alcoholic cardiomyopathy (ACM) compared with dilated cardiomyopathy (DCM) and were investigated in this study., Methods: Using Danish nationwide registries, a cohort analysis was conducted to assess the prognostic differences for patients with a first diagnosis of ACM versus DCM with and without AF 1994-2018 (followed until end 2019). Our study also assessed differences in mortality following initiation of anticoagulation in both populations., Results: Totally, 1237 patients with ACM (33% with AF) and 17,211 individuals with DCM (33% with AF) were included. Those with ACM were more often men (89 versus 71%) and younger than patients with DCM (mean age 56 versus 64 years). Cumulative 5-year mortality was greater among patients with ACM, compared with DCM, regardless of AF (ACM with AF 49% [95% CI: 44-54%], ACM without AF 48% [45-53%], DCM with AF 41% [39-42%], DCM without AF 30% [29-31%], P < 0.0001). The prognosis associated with AF was statistically significantly different in people with ACM and DCM (adjusted hazards ratio 0.85 [95% CI: 0.74-0.98] versus 1.04 [1.00-1.09] in ACM and DCM, P < 0.0001). The mortality associated with oral anticoagulation was similar in ACM and DCM (hazards ratio 0.81 [0.61-1.07] versus 0.87 [0.80-0.94], P = 0.49)., Conclusions: Patients with ACM had a worse prognosis when compared with patients with DCM, but this did not appear to be driven by AF. Patients with ACM were observed to have similar associated risk benefits of oral anticoagulation as DCM., (© The Author(s) 2022. Medical Council on Alcohol and Oxford University Press. All rights reserved.)

Objectives: In the randomized controlled trial PANTHEM, the prophylactic effect of oral amoxicillin or clindamycin is investigated in patients receiving chronic haemodialysis (HD). However, data on plasma concentrations of these antibiotics during HD are sparse. This study aims to determine if the plasma concentration of amoxicillin and clindamycin is sufficient during HD after oral administration of amoxicillin and clindamycin at three different time intervals prior to the HD procedure., Methods: Adult patients receiving chronic HD were investigated twice with an interval of at least 7 days starting with either a tablet of 500/125 mg amoxicillin/clavulanic acid or a tablet of 600 mg clindamycin. Patients were randomized to take the antibiotics either 30, 60 or 120 min prior to the HD procedure. Plasma antibiotic concentrations were measured at start, midway and at the end of HD. A lower threshold was set at 2.0 mg/L for amoxicillin and at 1.0 mg/L for clindamycin. In addition, a population pharmacokinetic (PK) analysis was performed, assessing PTA., Results: In the amoxicillin cohort (n = 37), 84% of patients and 95% of all plasma amoxicillin concentrations were above or at the threshold throughout the dialysis procedure. In the clindamycin cohort (n = 33), all concentrations were above the threshold throughout the dialysis procedure. Further, in all patients, the mean plasma concentration of both amoxicillin and clindamycin across the HD period was well above the threshold. Finally, the PK model predicted a high PTA in the majority of patients., Discussion: In patients on chronic HD, oral administration of amoxicillin/clavulanic acid (500/125 mg) or clindamycin (600 mg) within 30-120 min prior to HD leads to a sufficient prophylactic plasma concentration across the HD period., (© The Author(s) 2023. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy.)

Aims: The present study aimed to determine the association between Type 2 diabetes mellitus (T2DM) and third-degree (complete) atrioventricular block., Methods and Results: This nationwide nested case-control study included patients older than 18 years, diagnosed with third-degree atrioventricular block between 1 July 1995 and 31 December 2018. Data on medication, comorbidity, and outcomes were collected from Danish registries. Five controls, from the risk set of each case of third-degree atrioventricular block, were matched on age and sex to fit a Cox regression model with time-dependent exposure and time-dependent covariates. Subgroup analysis was conducted with Cox regression models for each subgroup. We located 25 995 cases with third-degree atrioventricular block that were matched with 130 004 controls. The mean age was 76 years and 62% were male. Cases had more T2DM (21% vs. 11%), hypertension (69% vs. 50%), atrial fibrillation (25% vs. 10%), heart failure (20% vs. 6.3%), and myocardial infarction (19% vs. 9.2%), compared with the control group. In Cox regression analysis, adjusting for comorbidities and atrioventricular nodal blocking agents, T2DM was significantly associated with third-degree atrioventricular block (hazard ratio: 1.63, 95% confidence interval: 1.57-1.69). The association remained in several subgroup analyses of diseases also suspected to be associated with third-degree atrioventricular block. There was a significant interaction with comorbidities of interest including hypertension, atrial fibrillation, heart failure, and myocardial infarction., Conclusion: In this nationwide study, T2DM was associated with a higher rate of third-degree atrioventricular block compared with matched controls. The association remained independent of atrioventricular nodal blocking agents and other comorbidities known to be associated with third-degree atrioventricular block., Competing Interests: Conflict of interest: S.H. reports educational grant from Medtronic covering conference fee to attend European Heart Rhythm association Congress 2022 in Copenhagen. C.T.P. reports grants from Bayer and Novo Nordisk unrelated to the current study. U.P.B. reports personal fee from Novo Nordisk and Sanofi for advisory work unrelated to current study. All other authors have nothing to disclose., (© The Author(s) 2022. 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.)

Aims: In a continuously ageing population of patients with congenital heart disease (CHD), understanding the long-term risk of morbidity is crucial. The aim of this study was to compare the lifetime risks of developing comorbidities in patients with simple CHD and matched controls., Methods and Results: Using the Danish nationwide registers spanning from 1977 to 2018, simple CHD cases were defined as isolated atrial septal defect (ASD), ventricular septal defect (VSD), pulmonary stenosis, or patent ductus arteriosus in patients surviving until at least 5 years of age. There were 10 controls identified per case. Reported were absolute lifetime risks and lifetime risk differences (between patients with simple CHD and controls) of incident comorbidities stratified by groups and specific cardiovascular comorbidities. Of the included 17 157 individuals with simple CHD, the largest subgroups were ASD (37.7%) and VSD (33.9%), and 52% were females. The median follow-up time for patients with CHD was 21.2 years (interquartile range: 9.4-39.0) and for controls, 19.8 years (9.0-37.0). The lifetime risks for the investigated comorbidities were higher and appeared overall at younger ages for simple CHD compared with controls, except for neoplasms and chronic kidney disease. The lifetime risk difference among the comorbidity groups was highest for neurological disease (male: 15.2%, female: 11.3%), pulmonary disease (male: 9.1%, female: 11.7%), and among the specific comorbidities for stroke (male: 18.9%, female: 11.4%). The overall risk of stroke in patients with simple CHD was mainly driven by ASD (male: 28.9%, female: 17.5%), while the risks of myocardial infarction and heart failure were driven by VSD. The associated lifetime risks of stroke, myocardial infarction, and heart failure in both sexes were smaller in invasively treated patients compared with untreated patients with simple CHD., Conclusion: Patients with simple CHD had increased lifetime risks of all comorbidities compared with matched controls, except for neoplasms and chronic kidney disease. These findings highlight the need for increased attention towards early management of comorbidity risk factors., Competing Interests: Conflict of Interest: Christian-Torp Pedersen has received grants for studies from Bayer and Novo Nordisk unrelated to the current study. Matthew Phelps has, after the initial submission of this paper, been employed by Novo Nordisk unrelated to this study. The other authors have no potential conflicts of interest to declare in relation to the publication this article., (© The Author(s) 2022. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Background and Aims: Chronic obstructive pulmonary disease (COPD) is present in 13% of atrial fibrillation (AF) patients. In patients diagnosed with both AF and COPD, we aimed to assess overall mortality risk and its association with temporal sequence in AF and COPD diagnosis., Methods: This nationwide study assessed all patients aged 18-85 years diagnosed with both COPD and AF between 1999 and 2018 in Denmark. Three groups were defined according to the temporal sequence of diagnosis: COPD diagnosed at least 6 months before AF (COPD-First), AF diagnosed at least 6 months before COPD (AF-First) and COPD, and AF diagnosed within a 6-months' time frame (AF∼COPD)., Results: We included 62 806 patients (75.0 years; 56.5% males). After 5 years of follow-up, 31 494 (50.1%) died. Mortality was highest in the COPD-First group (COPD-First: 52.8%; AF-First: 46.0%; AF∼COPD 50.6%). In a multivariable Cox-regression model adjusted for age, sex, type 2 diabetes, history of acute myocardial infarction, hypertension, heart failure, dyslipidemia, cancer, chronic kidney disease, and stroke, the AF∼COPD group (HR 1.19, 95% CI 1.16-1.23; P < 0.001) and COPD-First group (HR 1.30, 95% CI 1.27-1.33; P < 0.001) had a higher risk of death compared with the AF-First group. A restricted cubic spline analysis showed that the earlier the COPD was diagnosed, the worse is the prognosis., Conclusion: Patients with concomitant AF and COPD had a very poor prognosis and the temporal sequence in diagnosis was differentially associated with prognosis, where a COPD diagnosis preceding an AF diagnosis was accompanied with a higher mortality risk compared with a COPD diagnosis following an AF diagnosis., (© The Author(s) 2022. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Aims: Atrial fibrillation (AF) and heart failure (HF) often coexist. However, whether AF onset before HF or vice versa is associated with the worst outcome remains unclear. A consensus of large studies can guide future research and preventive strategies to better target high-risk patients., Methods and Results: We included all Danish cases with the coexistence of AF and HF (2005-17) using nationwide registries. Patients were divided into three separate groups (i) AF before HF, (ii) HF before AF, or (iii) AF and HF diagnosed concurrently (±30 days). Adjusting landmark Cox analyses (index date was the time of the latter diagnosis of AF or HF) were used for evaluating the association of the three groups with a composite outcome of ischaemic stroke or death. Among a total of 49 042 patients included, 40% had AF before HF, 27% had HF before AF, and 33% had AF and HF diagnosed concurrently. The composite endpoint accrued more often in patients with HF before AF compared to the two other groups (<0.001), and this remained significant in the adjusted analyses with hazard ratios (95% confidence intervals) of 1.26 (1.22-1.30) compared to AF before HF. Finally, antihypertensive treatment, oral anticoagulants, amiodarone, statins, and AF ablation were associated with a lower hazard ratio of the composite endpoint (all < 0.001)., Conclusions: In this large Danish national cohort, diagnosis of HF before AF was associated with an increased absolute risk of death compared to AF before HF and AF and HF diagnosed concurrently. Antihypertensive treatment, oral anticoagulants, amiodarone, statins, and AF ablation may improve prognosis., Competing Interests: Conflict of interest: P.M.O. acts as an advisor to Prolaio Inc. All remaining authors have declared no conflicts of interest.., (© The Author(s) 2022. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Aims: To investigate the association between the arrival of smartphone-activated volunteer responders before the Emergency Medical Services (EMS) and bystander defibrillation in out-of-hospital cardiac arrest (OHCA) at home and public locations., Methods and Results: This is a retrospective study (1 September 2017-14 May 2019) from the Stockholm Region of Sweden and the Capital Region of Denmark. We included 1271 OHCAs, of which 1029 (81.0%) occurred in private homes and 242 (19.0%) in public locations. The main outcome was bystander defibrillation. At least one volunteer responder arrived before EMS in 381 (37.0%) of OHCAs at home and 84 (34.7%) in public. More patients received bystander defibrillation when a volunteer responder arrived before EMS at home (15.5 vs. 2.2%, P < 0.001) and in public locations (32.1 vs. 19.6%, P = 0.030). Similar results were found among the 361 patients with an initial shockable heart rhythm (52.7 vs. 11.5%, P < 0.001 at home and 60.0 vs. 37.8%, P = 0.025 in public). The standardized probability of receiving bystander defibrillation increased with longer EMS response times in private homes. The 30-day survival was not significantly higher when volunteer responders arrived before EMS (9.2 vs. 7.7% in private homes, P = 0.41; and 40.5 vs. 35.4% in public locations, P = 0.44)., Conclusion: Bystander defibrillation was significantly more common in private homes and public locations when a volunteer responder arrived before the EMS. The standardized probability of bystander defibrillation increased with longer EMS response times in private homes. Our findings support the activation of volunteer responders and suggest that volunteer responders could increase bystander defibrillation, particularly in private homes., Competing Interests: Conflict of interest: L.A., C.M.H., M.C.T.G., and F.F. have received research grants from TrygFonden. C.M.H. has received research grants from Laerdal Foundation and Helsefonden. F.F. has received research grants from the Novo Nordisk Foundation and the Laerdal Foundation. L.K. has received speaker honoraria from AstraZeneca, Novo Nordisk, Boehringer, and Novartis. C.T.-P. has received research grants from Bayer and Novo Nordisk. A.C., J.H., and M.R. are shareholders in the HeartRunner app. Other authors have no disclosures to declare., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Aims: Outcomes after myocardial infarction (MI) improved during recent decades alongside better risk factor management and implementation of guideline-recommended treatments. However, it is unknown whether this applies to stable patients who are event-free 1 year after MI., Methods and Results: Using nationwide Danish registries, we included all patients with first-time MI during 2000-17 who survived 1 year free from bleeding and cardiovascular events (n = 82 108, median age 64 years, 68.2% male). Follow-up started 1 year after MI and continued through January 2022. Crude risks of mortality, cardiovascular events, and bleeding were estimated in consecutive 3-year periods. Standardized risks were calculated with respect to the distribution of age, sex, comorbidities, and treatments in the latter period. Guideline-recommended treatment use increased during the study period: e.g. statins (68.6-92.5%) and percutaneous coronary intervention (23.9-68.2%). The crude 5-year risks of outcomes decreased (all P-trend <0.001): Mortality, 18.6% (95% confidence interval [CI]: 17.9-19.2) to 12.5% (CI: 11.9-13.1); Recurrent MI, 7.5% (CI: 7.1-8.0) to 5.5% (CI: 5.1-6.0); Bleeding, 3.9% (CI: 3.6-4.3) to 2.7% (CI: 2.4-3.0). Crude 5-year risk of mortality in 2015-17 was as low as 2.6% for patients aged <60 years. Use of guideline-recommended treatments was associated with improved outcomes: After standardization for changes in treatments, 5-year risk of mortality in 2000-02 was 15.5% (CI: 14.9-16.2)., Conclusions: For patients who were event-free 1 year after MI, the long-term risks of mortality, cardiovascular events, and bleeding decreased significantly, along with an improved use of guideline-recommended treatments between 2000 and 2017. In the most recent period, 1 year after MI, the risk of additional events was lower than previously reported., Competing Interests: Conflict of interest: LS is employed by Novo Nordisk without relation to the current study. ACR reports aspeaker’s fee from Novartis. EF reports independent research grants from the Novo Nordisk Foundation and the Danish Heart Foundation without relation to the current study. LK reports speaker’s fees from Novo Nordisk, Novartis, Boehringer Ingelheim,AstraZeneca, and Bayer. CTP reports study grants from Bayer and Novo Nordisk without relation to the current study. MS reports lecture fees from Novo Nordisk, Astra Zeneca, Novartis, and Boehringer Ingelheim outside the current study. All author authors had no conflicts of interest to disclose., (© The Author(s) 2022. Published by Oxford University Press on behalf of the European Society of Cardiology.)