AM/PM dosing of LAMA for COPD: a randomized controlled trial protocol using digital recruitment and registries.

Rationale: Long-acting muscarinic antagonists (LAMAs) reduce the risk of acute exacerbations of chronic obstructive pulmonary disease (AECOPD), usually taken once daily in the morning. However, the circadian activity of autonomic regulation suggests that the highest need for anticholinergic therapy may be in the late night/early morning. This is supported by evidence that AECOPD most often begins in the morning. Furthermore, the trough spirometry effect of LAMA is lower than the peak effect, which further argues that evening dosing may be more optimal than morning dosing. This trial aims to determine whether evening administration of LAMA reduces hospitalization-requiring AECOPD or death from all causes within 1 year as compared to morning administration of the same LAMA. Methods: Randomized controlled open-label trial. Persons aged 30 years or older with a once-daily LAMA prescription and a confirmed COPD diagnosis were recruited. Participants were randomized in a 1:1 ratio to either morning or evening LAMA administration. Complete follow-up for the primary outcome, hospitalization-requiring AECOPD, or death from all causes within 1 year was captured from the Danish National Health Register, as were patient-reported outcome assessments at 6 and 12 months. Results: A total of 10,013 participants were randomized, and the recruitment process started on 9 March 2023. Secondary outcomes include (i) moderate COPD exacerbations; (ii) all-cause hospitalization; (iii) ICU admission; (iv) need for non-invasive ventilation; and (v) all-cause mortality, among others. All outcomes will be evaluated 12 months after recruitment.Clinical trial registration:ClinicalTrials.gov, NCT05563675.

Implications of Age for the Diagnostic and Prognostic Value of Cardiac Troponin T and I.

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.

Recurrent venous thromboembolism and vaginal estradiol in women with prior venous thromboembolism: A nested case-control study.

OBJECTIVES: Whether vaginal estradiol use is associated with an increased risk of recurrent venous thromboembolism (VTE) in women with prior VTE is unknown. We sought to evaluate the association between vaginal estradiol use and recurrent VTE in women with prior VTE. METHODS: We performed a nationwide nested case-control study among 44 024 women aged ≥45 years who developed a first VTE without a history of vaginal estrogen use prior to VTE diagnosis. Cases with recurrent VTE were matched 1:2 on birth year with controls using incidence density sampling. Exposure to vaginal estradiol tablets was categorized into current use (0-2 months before index), prior use (2-24 months before index) and past use (more than 24 months prior to index). RESULTS: We identified 5066 cases and 10 127 age-matched controls. In fully adjusted analysis vaginal estrogen was not associated with recurrent VTE with a hazard ratio of 0.75, p = .07 for current use, 0.83, p = .13 for prior use, and 1.24, p = .06 for past use. CONCLUSION: Use of vaginal estradiol tablets in women with prior VTE was not associated with an increased rate of recurrent VTE. Our study indicates that vaginal estradiol therapy is unlikely to increase risk of recurrent VTE in women with prior VTE.

Triglyceride-glucose index improves risk prediction beyond traditional risk factors and hypertension mediated organ damage in healthy adults.

BACKGROUND AND AIMS: Triglyceride-glucose (TyG) index, a surrogate measure of insulin resistance, is associated with hypertension mediated organ damage (HMOD) and cardiovascular disease. This study investigated the association between TyG index and major adverse cardiovascular events (MACE) and its interaction with traditional risk factors and HMOD. METHODS AND RESULTS: Healthy subjects recruited from the general population were thoroughly examined and followed for MACE using nation-wide registries. Cox proportional hazard models were used to calculate the association between TyG index and MACE occurrence. Models were adjusted for Systematic Coronary Risk Evaluation (SCORE) risk factors, pulse wave velocity, left ventricular mass index, carotid atherosclerotic plaque status, and microalbuminuria. Continuous net reclassification and Harrell's Concordance index (C-index) were used to assess the added prognostic value of TyG index. During a follow-up period of mean 15.4 ± 4.7 years, MACE were observed in 332 (17%) of 1970 included participants. TyG index was associated with MACE; HR = 1.44 [95%CI:1.30-1.59] per standard deviation. After adjustment for traditional cardiovascular (CV) risk factors, HR was 1.16 [95%CI:1.03-1.31]. The association between TyG index and MACE remained significant after further adjustment for each HMOD component. However, this finding was evident only in subjects aged 41 or 51 years (HR = 1.39; 95%CI:1.15-1.69). Including TyG index in a risk model based on traditional CV risk factors improved C-index with 0.005 (P = 0.042). CONCLUSION: In this population-based study of healthy middle-aged subjects, TyG index was associated with MACE independently of traditional CV risk factors and HMOD. TyG index may have a potential role in future risk prediction systems.

Long-term aspirin adherence following myocardial infarction and risk of cardiovascular events.

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.

Antithrombotic treatment for chronic coronary syndrome: Evidence and future perspectives.

Background The clinical presentation of coronary artery disease can range from asymptomatic, through stable disease in the form of chronic coronary syndrome, to acute coronary syndrome. Chronic coronary syndrome is a frequent condition, and secondary prevention of ischaemic events is essential. Summary Antithrombotic therapy is a key component of secondary prevention strategies, and it may vary in type and intensity depending on patient characteristics, comorbidities, and revascularisation modalities. Dual antiplatelet therapy is the default strategy in patients with chronic coronary syndrome and recent coronary stent implantation, while antiplatelet monotherapy is commonly prescribed for long-term prevention of cardiovascular events. Oral anticoagulation, in combination with antiplatelet therapy or alone, is used in patients with e.g., concomitant atrial fibrillation or venous thromboembolism. Key messages This review provides an overview of antithrombotic treatment strategies in patients with chronic coronary syndrome. Key messages from current guidelines are conveyed, and we provide future perspectives on long-term antithrombotic strategies.

N-Terminal Pro-Brain Type Natriuretic Peptide Predicts Cardiovascular Events Independently of Arterial Stiffness, Assessed By Carotid-to-Femoral Pulse Wave Velocity, in Apparently Healthy Subjects.

AIM: This study aimed to evaluate whether N-terminal pro-brain natriuretic peptide (NT-proBNP) and carotid-to-femoral pulse wave velocity (PWV) carried independent prognostic value in predicting cardiovascular events in apparently healthy individuals beyond traditional risk factors. METHODS: A total of 1,872 participants aged 41, 51, 61, or 71 years from the MONItoring of trends and determinants in CArdiovascular disease (MONICA) study were included. Traditional risk factors were assessed, including: smoking status; mean systolic and diastolic blood pressure; body mass index; fasting plasma glucose; serum triglycerides; total, high-density, and low-density lipoprotein cholesterol; NT-proBNP; and PWV. The principal endpoint that was assessed during 16 years of follow-up was a composite of major adverse cardiovascular events (MACE). The secondary endpoints were cardiovascular mortality (CVM), hospitalisation for coronary artery disease (CAD), and a composite of hospitalisation for heart failure (HF) or atrial fibrillation (AF). RESULTS: At baseline, NT-proBNP was associated with PWV (ß=0.14; p<0.001), but not after adjustment for traditional risk factors (ß=-0.01; p=0.67). In models including traditional risk factors and PWV, NT-proBNP was associated with all four outcomes (HRMACE=1.33, 95% CI 1.16-1.52; HRCVM=2.02, 95% CI 1.65-2.48; HRCAD=1.29, 95% CI 1.07-1.55; and HRHF or AF=1.79, 95% CI 1.40-2.28). In the same model, PWV was only associated with CVM (HRCVM=1.20, 95% CI 1.01-1.41). No interactions between NT-proBNP and PWV were found. N-terminal pro-brain natriuretic peptide significantly improved net reclassification (NRI) for MACE (NRI=0.12; p=0.03), CVM (NRI=0.33; p<0.001), and HF or AF (NRI=0.33; p<0.001) beyond traditional risk factors, while PWV did not aid in net reclassification improvement for any endpoint. CONCLUSIONS: In apparently healthy individuals, NT-proBNP and PWV predicted cardiovascular events independently. N-terminal pro-brain natriuretic peptide improved reclassification for the prediction of MACE, CVM, and hospitalisation for HF or AF beyond traditional risk factors, while PWV did not.

Temporal trends in characteristics and outcomes after myocardial infarction in patients with and without peripheral artery disease - A Nationwide, register-based follow-up study.

AIM: Patients with peripheral artery disease (PAD) represent a high-risk population with increased morbidity and mortality. We aimed to examine trends in myocardial infarction (MI), PAD and adverse clinical outcomes from years 2000 to 2019. METHODS: This nationwide Danish-based registry study included all patients with MI from years 2000-2019. Patients with PAD were compared to patients without PAD. Temporal changes in PAD prevalence over time was examined using the Cochrane-Armitage trend test, and Cox regression was used to test for between-group significance in all care and outcome measures. RESULTS: A total of 196,635 patients experienced an MI within the study time frame; the prevalence of PAD over time showed a slight increase (p < 0.01). Patients with MI and a concurrent PAD diagnosis elicited a heavier burden of comorbidities. The primary MACE endpoint showed significant decreases in both patients with and without PAD (p < 0.01); the decrease was more marked in patients without a concurrent PAD diagnosis (p < 0.01) alongside with 1-year all-cause mortality (p < 0.01). There was a slight increase in initiation of preventive pharmacotherapy with a prominent increase in initiation of P2Y12-inhibitors post discharge in patients without PAD in comparison to patients with PAD, and the same pattern applied for lipid lowering agents (p < 0.01). Also, there was an increase in revascularization in patients with MI but more markedly in patients without coexisting PAD. CONCLUSIONS: Despite significant decreases in MACE and mortality and significant increases in guideline-recommended care and revascularization over time for MI patients both with and without PAD, improvement in all these measures was less prominent in patients with MI and concomitant PAD.

Ticagrelor or prasugrel vs. clopidogrel in patients with atrial fibrillation undergoing percutaneous coronary intervention for myocardial infarction.

Aims: The efficacy and safety of ticagrelor or prasugrel vs. clopidogrel in patients with atrial fibrillation (AF) on oral anticoagulation (OAC) undergoing percutaneous coronary intervention (PCI) for myocardial infarction (MI) have not been established. Methods and results: This was a nationwide cohort study of patients on OAC for AF who underwent PCI for MI from 2011 through 2019 and were prescribed a P2Y12 inhibitor at discharge. The primary efficacy outcome was major adverse cardiovascular events (MACE), defined as a composite of death from any cause, stroke, recurrent MI, or repeat revascularization. The primary safety outcome was cerebral, gastrointestinal, or urogenital bleeding requiring hospitalization. Absolute and relative risks for outcomes at 1 year were calculated through multivariable logistic regression with average treatment effect modelling. Outcomes were standardized for the individual components of the CHA2DS2-VASc and HAS-BLED scores as well as type of OAC, aspirin, and proton pump inhibitor use. We included 2259 patients of whom 1918 (84.9%) were prescribed clopidogrel and 341 (15.1%) ticagrelor or prasugrel. The standardized risk of MACE was significantly lower in the ticagrelor or prasugrel group compared with the clopidogrel group (standardized absolute risk, 16.3% vs. 19.4%; relative risk, 0.84, 95% confidence interval, 0.70-0.98; P = 0.02), while the risk of bleeding did not differ (standardized absolute risk, 5.5% vs. 5.1%; relative risk, 1.07, 95% confidence interval, 0.73-1.41; P = 0.69). Conclusion: In patients with AF on OAC who underwent PCI for MI, treatment with ticagrelor or prasugrel vs. clopidogrel was associated with reduced ischaemic risk, without a concomitantly increased bleeding risk.