Background Clinical and translational research suggests that mineralocorticoid receptor antagonists (MRAs) may prevent atrial fibrosis and electrical remodeling associated with atrial fibrillation (AF). This study aimed to consolidate existing evidence from randomized controlled trials (RCTs) evaluating the effect of MRAs on incident or recurrent AF. Methods Medline, Cochrane Library and Scopus were searched until February 12, 2024. Triple-independent study selection, data extraction and quality assessment were performed. Evidence was pooled using both pairwise and Bayesian and frequentist network meta-analyses. Results Twenty-three RCTs (13,358 participants) were identified. Based on the pairwise random effects meta-analysis, MRAs were associated with a significant reduction in AF events compared to placebo or usual care (risk ratio {RR}= 0.75; 95% confidence interval {CI}= [0.66, 0.87]; P< 0.001; I2= 3%). This protective effect was robust both for new-onset and recurrent AF episodes (subgroup p-value= 0.69), while the baseline HF status was not a significant effect modifier (subgroup p-value= 0.58). MRAs demonstrated a significantly higher reduction in AF events for patients with chronic renal disease compared to placebo (RR= 0.78; 95% CI= [0.62, 0.98]; P= 0.03; I2= 0%). The network meta-analyses revealed that only spironolactone was associated with a significant reduction in AF events (Bayesian RR= 0.76; 95% CI= [0.65, 0.89]; P< 0.001; level of evidence moderate; SUCRA 0.731), while eplerenone and finerenone showed a neutral effect. Conclusion MRAs confer a significant benefit in terms of reducing incident or recurrent AF episodes, irrespective of HF status. In this context, spironolactone may be preferable compared to eplerenone or finerenone.

Abstract Funding Acknowledgements None. Background The GRACE 3.0 (GRS 3.0) is a risk assessment tool for in hospital mortality for patients admitted with acute coronary syndrome (ACS). This study sought to validate the accuracy of GRS 3.0 in predicting long-term mortality following a hospitalization for ACS. Methods We measured retrospectively all various factors included in GRS 3.0 such as age, heart rate, systolic blood pressure, creatinine, sex, cardiac arrest, ST-segment deviation on ECG, troponin elevation, and Killip Class. Multivariable Cox regression analysis was used. The discriminative ability of the GRACE 3.0 risk score was calculated by the c-index, which corresponds to the area under the ROC curve. Results 223 patients with ACS were included. During a median follow-up of 3 years, 57 (25.6%) patients died. Among the variables of GRS 3.0, age, heart rate, and troponin elevation at admission were the only independent predictors of mortality. The score had good discrimination for all-cause mortality (c-index=0.82, 95% CI 0.75–0.89) [Figure]. It performed equally well in both sexes. Conclusions The newly developed GRS 3.0 is well-performing for predicting long-term mortality in patients hospitalized for ACS. Thus, it may assist in tailored risk stratification and management of these patients following hospital discharge.

Abstract Introduction Delayed implementation of new medical discoveries remains a global healthcare challenge and is mainly due to the complexity of cross-institutional patient care. Sodium-glucose co-transporter-2 (SGLT-2) inhibitors is the latest medical discovery in heart failure (HF) and have recently been added to clinical guidelines as they have proven to reduce the risk of adverse cardiovascular outcomes in patients with HF across the ejection fraction spectrum. Whether a new digital strategy can optimise and accelerate the implementation of SGLT2 inhibitors in patients living with HF is of great importance for public health. Purpose To evaluate whether a new and streamlined digital strategy can optimise and accelerate the implementation of SGLT2 inhibitors in patients with HF. Design and methods: The trial is a multicentre, parallel group, register-based randomised clinical study, evaluating the effect and potential of a new digital strategy to implement new guideline therapies to patients living with a chronic disease, specifically SGLT2 inhibitors to patients with HF (figure 1). The setup employs data from nationwide health registers and official digital letters to inform patients about the new therapy option and invite them to have their eligibility evaluated by a HF specialist and start therapy. A total of ~10,000 patients with HF across the ejection fraction spectrum (with and without diabetes), who have not yet been started on SGLT2 inhibitors, are identified through Danish nationwide health registers, and randomised 1:1 to receive the digital letter (figure 2). The primary outcome is the proportion of patients redeeming a prescription of a SGLT2 inhibitor within six months. Secondary outcome is a composite HF endpoint consisting of all-cause death or HF hospitalisation. Other outcome measures are renal failure, stroke and myocardial infarction, safety outcomes, adherence to therapy and proportion of vulnerable patient groups initiating therapy including immigrants, elderly, frail patients, patients with lower socioeconomic level and lower educational level. A total of 4689 patients have been randomised (February 2024) and data will be presented in 2025. Conclusions The trial will determine the efficacy and safety of a new and streamlined digital strategy to implement SGLT2 inhibitors to patients with chronic HF. The setup has the potential to be used in a broad spectrum of patients living with chronic diseases and is expected to be highly cost-effective.Figure 1.Study hypothesisFigure 2.Study design

Abstract Backround Atrial tachyarrhythmias (ATs) are frequently inter-related with heart failure (HF). ATs exacerbate HF, while the existence of chronic HF precipitates the occurrence of ATs. Landiolol, a highly selective and exceptionally-short acting beta-1 blocker has been used in patients with ATs and HF, where evidence on the available treatment options is limited. Purpose In this meta-analysis we intended to assess the clinical effects of rate control with landiolol in patients with ATs and comorbid left ventricular dysfunction, who are not septic or in peri-operative stage. Materials and Methods We systematically searched PubMed, Scopus and WebofScience up to 14 July 2023. Two independent reviewers screened and selected randomized control trials as well as observational studies according to predetermined eligibility criteria. Risk of bias and quality of evidence were assessed according to Cochrane guidelines. Results 2278 articles were initially screened and 11 studies were finally included in this systematic review. In 7 of the eligible studies landiolol was compared with placebo, while in the remaining 4 studies landiolol was investigated in comparison with other antiarrhythmic drugs and specifically digoxin and diltiazem. The total sample size included 1876 patients, 75% of whom were classified into III/IV NYHA class. Landiolol treatment reduced patients’ heart rate by a mean of 42 beats per minute (95% CI: 37-47 bpm) while 3 out of 4 treated patients accomplished targeted heart rate, described as an at least 20% reduction from baseline heart rate and final heart rate less than 110bpm. Compared to patients receiving other antiarrhythmic therapy, patients treated with landiolol had increased odds of achieving target heart rate (OR: 5.32, 95% CI: 2.87-10.05). Referring to landiolol safety, 15% of the treated patients encountered an adverse event, more frequently dose-dependent hypotension. Landiolol was discontinued only in a 6% of the treated patients. No difference in adverse events was identified between landiolol and other antiarrhythmic drugs. Conclusion In this meta-analysis landiolol has achieved satisfactory levels of efficacy and safety regarding rate control in patients with ATs and left ventricular dysfunction.Prisma FlowchartLandiolol efficacy in single-arm studies

Abstract Background Thyroid disease (THD) has often been associated with atrial fibrillation (AF) triggering, through endocrine mechanisms. Still, data on the impact of hypothyroidism on AF are contradictory. Our aim was to correlate the THD profile with the incidence of hard clinical endpoints in AF patients. Methods This post- hoc analysis of the MISOAC-AF RCT included hospitalized patients with AF and available history of THD. Patients were classified by categories of thyroid disease history (hyperthyroidism, hypothyroidism, euthyroidism). Unadjusted and adjusted hazard ratios (aHRs) were calculated using Cox regression models. Comparison groups included euthyroid compared to hypothyroid and hyperthyroid AF patients, respectively. All-cause mortality, cardiovascular death (CVD) and hospitalizations were the outcomes of interest. Survival analysis with the Kaplan-Meier curves was performed to analyze time-to-event data. Results A total of 496 AF patients followed-up for a mean of 2.7 years period, had available THD history and were included in the study. Of them, 16 patients (3.2%) were hyperthyroid, 141 (28.4%) hypothyroid, and 339 (68.4%) euthyroid. Patients with hypothyroidism had higher hospitalization rates during follow-up (aHR: 1.57, 95% CI: 1.12 to 2.20, p=0.008, p=0.025) compared to the euthyroid group. Higher TSH levels were correlated with an increased risk of CVD (aHR: 1.03, 95%CI: 1.01 to 1.05, p=0.007) and hospitalizations (aHR: 1.06, 95%CI: 1.01 to 1.12, p=0.03), while lower T3 levels were correlated with higher all-cause mortality rates (aHR: 0.51, 95%CI: 0.31 to 0.82, p=0.006) and CVD risk (aHR: 0.42, 95%CI: 0.23 to 0.77, p=0.005). Conclusions In AF patients, hypothyroidism was associated with increased hospitalizations, while elevated TSH levels and decreased T3 levels were associated with increased CVD and all-cause mortality respectively.Hypothyroidism and clinical outcomes

Abstract Aims Myocardial infarction with non-obstructive coronary arteries (MINOCA) is a clinical entity with several causes and pathophysiologic mechanisms. Secondary prevention with medical therapy used in patients with obstructive coronary artery disease has unclear benefits in MINOCA patients. Methods and results A literature search was conducted until 8 March 2022. Random-effect frequentist and hierarchical Bayesian meta-analyses were performed to assess the clinical impact of medical therapy [renin–angiotensin–aldosterone system (RAAS) inhibitors, statins, dual antiplatelet therapy (DAPT), β-blockers] in MINOCA patients. Outcomes of interest were all-cause mortality and major adverse cardiovascular events (MACE). A total of 12 663 MINOCA patients among five observational studies were analysed. The mean follow-up ranged from 12 to 90 months across studies. In frequentist meta-analysis, statins and β-blockers were associated with a lower risk of all-cause mortality [pooled adjusted hazard ratios (aHRs) 0.53 and 0.81, with 95% confidence intervals (CIs) (0.37–0.76) and (0.67–0.97), respectively]. Only RAAS inhibitors were associated with a lower risk of MACE [pooled aHR: 0.69, with 95% CI (0.53–0.90)]. Bayesian meta-analysis based on informative prior assumptions offered strong evidence only for the benefit of statins on decreasing the risk of all-cause death [Bayes factor (BF): 33.2] and moderate evidence for the benefit of RAAS inhibitors on decreasing the risk of MACE (BF: 9); assigning less informative prior distributions did not affect the results, yet it downgraded the level of evidence to anecdotal. Conclusion In this meta-analysis, statins and RAAS inhibitors were consistently associated with a lower risk of all-cause mortality and MACE, respectively, in patients with MINOCA. Neutral prognostic evidence was demonstrated for β-blockers and DAPT.

AIMS:We aimed to assess the impact of an educational, motivational intervention on the adherence to oral anticoagulation (OAC) in patients with non-valvular atrial fibrillation (AF). METHODS AND RESULTS:Hospitalized patients with non-valvular AF who received OAC were randomly assigned to usual medical care or a proactive intervention, comprising motivational interviewing, and tailored counselling on medication adherence. The primary study outcome was adherence to OAC at 1 year, which was evaluated according to proportion of days covered (PDC) by OAC regimens and was assessed through nationwide registers of prescription claims. Secondary outcomes included the rate of persistence to OAC, gaps in treatment, and clinical events. A total of 1009 patients were randomized, 500 in the intervention group and 509 in the control group. At 1-year follow-up, 77.2% (386/500) of patients in the intervention group were adherent (PDC > 80%), compared with 55% (280/509) in the control group [adjusted odds ratio (aOR) 2.84, 95% confidence interval (CI) 2.14-3.75; P < 0.001]. Mean PDC ± standard deviation was 0.85 ± 0.26 and 0.75 ± 0.31, respectively (P < 0.001). Patients that received the intervention were more likely to persist in their OAC therapy at 1 year (aOR 2.42, 95% CI 1.71-3.41; P < 0.001). Usual medical care was associated with more major (≥3 months) treatment gaps (aOR 2.39, 95% CI 1.76-3.26; P < 0.001). Clinical events over a median follow-up period of 2 years did not differ among treatment groups. CONCLUSION:In patients receiving OAC therapy for non-valvular AF, a multilevel motivational intervention significantly improved medication adherence and rate of therapy persistence, and reduced major gaps in treatment. No significant impact on clinical outcomes was observed. TRIAL REGISTRATION NUMBER:NCT02941978.

Abstract Funding Acknowledgements Type of funding sources: None. OnBehalf MISOAC- AF study group BACKGROUND Digoxin is widely used in atrial fibrillation (AF) and heart failure (AF). However, established evidence is conflicting regarding its association with clinical outcomes. AIM To investigate the relation between digoxin and adverse outcomes in patients with AF, with or without HF, in a contemporary AF cohort. METHODS We performed a retrospective analysis of data from 698 patients, originating from the MISOAC- AF (Motivational Interviewing to Support Oral AntiCoagulation Adherence in patients with non-valvular Atrial Fibrillation) trial, and followed over a median of 2.5 years. HF was denoted at baseline. The primary outcome was all-cause mortality and the secondary outcome was all-cause hospitalization, in a time-to-event analysis. Propensity scores were used to derive matched populations, balanced on key baseline covariates. To limit potential confounding, we also implemented inverse probability of treatment weighting (IPTW) analysis. RESULTS Among patients with HF, 10.5% (n = 39) were administered digoxin at baseline, whereas 89.5% (n = 331) were not. Digoxin administration was not associated with an increased risk of death (hazard ratio (HR) in the digoxin group, 1.21; 95% Confidence Interval (CI), 0.69 to 2.13, p = 0.5) or hospitalization of any cause (HR 1.15; 95% CI, 0.67 to 1.96; p = 0.6). Among patients without HF, 3.5% (n = 11) were administered digoxin, with neutral effects on all-cause mortality (HR: 3.25; 95% CI, 0.98 to 10.70), p = 0.06) and all-cause hospitalization (HR, 1.15; 95% CI, 0.67 to 1.96, p = 0.60). Consistent qualitatively results were observed using IPTW. CONCLUSIONS Among patients with AF, digoxin administration was not associated with an increased risk of death and hospitalization of any cause, irrespective of HF status. Abstract Figure.

Abstract Funding Acknowledgements Type of funding sources: None. Background Polypharmacy has been defined as the daily use of more than 4 drugs, by an individual, regardless of the condition(s) they have been prescribed for and their efficacy. The burden of polypharmacy pertains to adverse drug reactions, disability, frequent and longtime hospitalization and long-term mortality. The prevalence of polypharmacy exceeds 10% in most adult age groups and particularly in the elderly. At the same time, atrial fibrillation (AF) is the most prevalent sustained cardiac arrhythmia, afflicting more than 8% of the elderly and those with multiple comorbidities. Purpose The purpose of this study was to examine the association between the presence of polypharmacy and outcomes among AF patients. Methods This is a retrospective analysis among 1140 patients enrolled in the MISOAC-AF trial. All cause- and cardiovascular- mortality have been defined as primary endpoints. Independent clinical predictors of polypharmacy and of major adverse outcomes were identified via bootstrapped multivariate logistic and Cox regression analysis, respectively. Results The mean number of prescribed medications at patients’ discharge was 3.9 ± 1.6 and polypharmacy (use of more than 4 medications daily) was found in 36.9% of the patients. Smoking (p = 0.036), dyslipidemia (p < 0.001), coronary artery disease (p < 0.001), heart failure (HF; p = 0.003) and chronic kidney disease (p < 0.001) were independent predictors of polypharmacy among AF paients. Kaplan–Meier survival analysis showed that AF patients with polypharmacy have significantly greater risk of CV death (p = 0.040), while Cox regression analysis indicated polypharmacy as an independent predictor for all-cause and CV- mortality [adjusted hazard ratios: 1.31(1.03 - 1.67) and 1.39(1.05 - 1.84), respectively] and for the composite outcome of AF- or HF- related hospitalization or CV death [adjusted hazard ratio: 1.31 (1.05 - 1.63)]. Conclusion This study highlights the implications of polypharmacy in the context of AF, a prevalent, chronic, life-threatening condition. Investigating polypharmacy is quite relevant in the era of pharmacovigilance, contributing to rational pharmacotherapy with regard to cardiovascular conditions and beyond. Abstract Figure. Mortality rates by polypharmacy presence

The association of heart failure (HF) with the prognosis of atrial fibrillation (AF) remains unclear. OBJECTIVES To assess all-cause mortality in patients following hospitalization with comorbid AF in relation to the presence of HF. We performed a cross-sectional analysis of data from 977 patients discharged from the cardiology ward of a single tertiary center between 2015 and 2018 and followed for a median of 2 years. The association between HF and the primary endpoint of death from any cause was assessed using multivariable Cox regression. HF was documented in 505 (51.7%) of AF cases at discharge, including HFrEF (17.9%), HFmrEF (16.5%) and HFpEF (25.2%). A primary endpoint event occurred in 212 patients (42%) in the AF-HF group and in 86 patients (18.2%) in the AF-no HF group (adjusted hazard ratio [aHR] 2.27; 95% confidence interval [CI], 1.65 to 3.13; P<0.001). HF was associated with a higher risk of the composite secondary endpoint of death from any cause, AF or HF-specific hospitalization (aHR 1.69; 95% CI 1.32 to 2.16 p<0.001). The associations of HF with the primary and secondary endpoints were significant and similar for AF-HFrEF, AF-HFmrEF, AF-HFpEF. HF was present in half of the patients discharged from the hospital with comorbid AF. The presence of HF on top of AF was independently associated with a significantly higher risk of all-cause mortality than did absence of HF, irrespective of HF subtype. Type of funding source: None

Abstract Background Prior risk stratification schemes for atrial fibrillation (AF) have extensively focused on stroke as the principal outcome. However, an accurate estimation of the risk of death in patients with AF has received disproportional attention. Purpose The aim of this study was to develop and validate a risk score for predicting mortality in patients with AF who underwent a hospitalization for cardiac reasons. Methods The new risk score was developed and internally validated in 887 patients with AF, who were followed up for a median of 2 years. The outcome measure was all-cause mortality. Biomarker samples, echocardiographic data and renal function values were obtained at the date closest to hospital discharge. A Cox-model that determined the variables that significantly contributed to the prediction of all-cause mortality, was adapted to a risk points system through weighting of the model coefficients. The model was internally validated by bootstrapping, assessing both discrimination and calibration. Results 311 all-cause deaths were reported during 1755 person-years of follow-up (incidence rate 17.7 events per 100 person-years). The most important predictors of death were N-terminal pro B-type natriuretic peptide (NT-proBNP), high-sensitivity troponin-T (hs-TnT), left atrial area indexed to body surface area (LAAi), prior cardiac arrest, kidney impairment, congestive heart failure and age, and were included in the BLACCK (AF) death risk score. The score was well-calibrated (observed probabilities adjusted to predicted probabilities) and showed good discriminative ability [c-index 0.87 (95% CI 0.85–0.90)]. The internal validation of the score reported minimal over-fitting (optimism-corrected c-index of 0.85). The 1, 2 and 3-year risk of death derived by the score's total points may be calculated immediately through the nomogram (Figure 1). BLACCK (AF) risk score nomogram Conclusions We developed a simple, well-calibrated and internally validated novel risk score for predicting 1, 2 and 3-year risk of death in patients with AF after a hospitalization for cardiac reasons. The BLACCK (AF) death risk score included both cardiac biomarkers and clinical information, performed well and may assist physicians in decision-making when treating patients with AF.