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Background Heart failure (HF) is an established risk factor for stroke and systemic embolic events (SEE) in subjects with atrial fibrillation (AF), but it is debated whether this risk varies according to left ventricular ejection fraction (LVEF). Methods We investigated the impact of HF in the ETNA-AF-Europe registry, a prospective, multi-centre, post-authorisation, observational study enrolling patients treated with edoxaban for AF in 825 sites from 10 European countries. This 2-year follow-up analysis is based on a data snapshot from 26 October 2020. HF was defined as a) history of HF or b) ischaemic cardiomyopathy or c) EF Results Of the 13,133 patients, 1,854 (14.1%) had HF; LVEF was available for 1,489 (80.3%), and was When patients with HF were categorized according to LVEF, ischaemic stroke/TIA/SEE was more frequent in those with LVEF ≥40% vs those with LVEF Univariable Cox regression analysis confirmed the association of HF with major bleeding (HR 2.01, 95% CI [1.49–2.71]) and all-cause death (2.62 [2.28–3.02]), but not with ischaemic stroke/TIA/SEE (1.06 [0.72–1.55]). The results were consistent when LVEF was taken into account: the HRs for LVEF Conclusions In this real-world, large cohort of patients with AF on edoxaban, those with HF at baseline faced more ischaemic, bleeding, and death events, and having HF increased the risk of major bleeding and death, with no differences according to LVEF. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): This research was funded by Daiichi Sankyo Europe.

Introduction Dual antiplatelet therapy (DAPT) with aspirin and a P2Y12 receptor inhibitor for at least 1 month is the mainstay of therapy after an acute coronary syndrome (ACS). Despite several randomized controlled trials (RCTs) having compared different DAPT regimens after an ACS, the choice of the optimal P2Y12 receptor inhibitor is still debated. Purpose We aimed to compare the efficacy and safety profiles of the new P2Y12 receptor inhibitors (prasugrel and ticagrelor) versus clopidogrel in patients with ACS through a meta-analysis of RCTs. Methods We performed an extensive literature search, from January 1970 to December 2021 using PubMed database. Studies were eligible if they were RCTs directly comparing different oral P2Y12 receptor inhibitors in patients with ACS. Data on study methods, patient characteristics, and outcomes of interest (all-cause and cardiovascular death, recurrent myocardial infarction, stroke, major and non-major bleeding) were extracted from the original publications. We performed a meta-analysis using a random-effects model with the Mantel–Haenszel method. The effect measures of each study included were calculated and reported as odds ratio (OR) with 95% confidence interval (CI), visually presented in forest plots. A two-sided p-value Results A total of 117 studies were available for the analysis; after full reading 11 studies were eligible to be analyzed. The 11 studies reported data on 50,722 patients: 25,424 [50.1%] taking a new oral P2Y12 receptor inhibitor and 25,298 [49.9%] taking clopidogrel. Patients receiving ticagrelor or prasugrel showed a lower risk of all-cause mortality (OR 0.88, 95% confidence interval [CI] 0.80–0.97, I2=8%), cardiovascular mortality (OR 0.88, 95% CI 0.81–0.95, I2=0%), and recurrent myocardial infarction (OR 0.86, 95% CI 0.76–0.97, I2=43%) compared to those receiving clopidogrel. The two groups did not differ significantly concerning the risk of stroke (OR 0.98, 95% CI 0.82–1.17, I2=0%), major bleeding (OR 1.05, 95% CI 0.97–1.15, I2=0%), or non-major bleeding (OR 1.36, 95% CI 0.85–2.20, I2=67%). By restricting the analysis to the studies comparing ticagrelor versus clopidogrel, the ticagrelor group showed a lower risk of all-cause mortality (OR 0.79, 95% CI 0.70–0.90, I2=0%), but a higher risk of non-major bleeding (OR 1.67, 95% CI 1.05–2.66, I2=30%). There was no significant difference between ticagrelor and clopidogrel in terms of cardiovascular death (OR 0.87, 95% CI 0.73–1.05, I2=0%), stroke (OR 1.06, 95% CI 0.85–1.13, I2=0%), or major bleeding (OR 1.02, 95% CI 0.93–1.12, I2=0%). Conclusions In patients with an ACS, a DAPT strategy with aspirin plus either prasugrel or ticagrelor is associated with a reduced risk of all-cause and cardiovascular mortality as well as of recurrent myocardial infarction compared to aspirin plus clopidogrel, without an increased risk of bleeding. Funding Acknowledgement Type of funding sources: None.

Background Whether revascularization reduces ischemic events and improves prognosis in patients with chronic coronary artery syndrome (CCS) without left main (LM) disease or reduced left ventricle ejection fraction (LVEF) remains a topic of debate. Nevertheless, the impact of revascularization on outcomes in patients with CCS may be influenced by the revascularization strategy adopted. Purpose We aimed at evaluating the comparative effects of different revascularization strategies in patients with CCS. Methods A total of 18 randomized controlled trials including angiography-guided percutaneous coronary intervention (PCI), physiology-guided PCI and coronary artery bypass graft (CABG), were included. Effect estimates included direct comparisons for all treatments and direct and indirect evidence were in agreement for all included outcomes, fulfilling the consistency assumption. Incidence rate ratios (IRR) and associated 95% confidence intervals (CIs) were used to adjust outcomes according to follow-up durations. Medical therapy was used as reference strategy. Results Compared with medical therapy, at a mean follow-up of 5.1 years, all revascularization strategies were associated with a reduction of the primary endpoint, as defined in each trial, the extent of which was modest with angiography-guided PCI (IRR 0.86, 95% CI 0.75–0.99) and greater with physiology-guided PCI (IRR 0.60, 95% CI 0.47–0.77) and CABG (IRR 0.58, 95% CI 0.48–0.70). Moreover, angiography-guided PCI was associated with increased primary endpoint compared to physiology-guided PCI (IRR 1.43, 95% CI 1.14–1.79) and CABG (IRR 1.49, 95% CI 1.27–1.74). CABG was the only strategy associated with reduced myocardial infarction (IRR 0.68, 95% CI 0.52–0.90), cardiovascular death (IRR 0.76, 95% CI 0.64–0.89), and all-cause death (IRR 0.87, 95% CI 0.77–0.99), but increased stroke (IRR 1.69, 95% CI 1.04–2.76). Results were consistent at secondary analysis exploring the impact on outcomes of baseline characteristics, such as 3-vessel disease, diabetes mellitus, year of publication or stents used. Conclusions In CCS patients without LM disease or reduced LVEF, physiology-guided PCI and CABG were associated with better outcomes than angiography-guided PCI. Compared with medical therapy, CABG was the only revascularization strategy associated with a reduction of myocardial infarction and death rates, at the cost of higher risk of stroke. Funding Acknowledgement Type of funding sources: None.

Background/Introduction Concomitant diabetes mellitus (DM) in patients with atrial fibrillation (AF) has been associated with a higher risk of stroke/systemic embolic events (SEE), and higher mortality. Purpose To evaluate effectiveness and safety outcomes in AF patients with different types of concomitant DM vs those without concomitant DM after 2 years of edoxaban treatment in a sub-analysis of the prospective ETNA-AF-Europe registry. Methods Patients with AF who received edoxaban once daily were enrolled across 825 centres in 10 European countries. This sub-analysis is based on a data snapshot from 26th October 2020. Patients were grouped by DM status (with or without DM; insulin-treated or non-insulin-treated DM). Baseline characteristics are summarised descriptively. Kaplan-Meier (KM) survival curves of outcomes were constructed; annualised event rates (AERs; %/year) and comparisons between patients with or without DM by univariate analysis are presented. Comparisons of patients with insulin- vs non-insulin-treated DM were made by multivariate analysis adjusted for HbA1c. Results Patients' demographics and baseline characteristics are shown in Table 1. Of 13,133 patients with AF, 2885 (22.0%) had DM. Among patients with DM, 2756 (95.6%) received treatment: 605 (22.0%) with insulin and 2151 (78.0%) with non-insulin treatments. KM curves for effectiveness and safety outcomes are shown in Figure 1. AERs (%/year) of ischaemic stroke/transient ischaemic attack (TIA)/SEE were 0.86% in patients with AF and no DM, 0.87% with non-insulin-treated DM (p=0.9216 vs no DM) and 1.81% with insulin-treated DM (p=0.0022 vs no DM; p=0.0014 vs non-insulin-treated DM). AERs of myocardial infarction (MI) were 0.40%, 0.43% (p=0.7454 vs no DM), and 1.04% (p=0.0033 vs no DM) respectively; of major bleeding were 0.90%, 1.10% (p=0.2427 vs no DM), and 1.71% (p=0.0106 vs no DM), respectively; and of all-cause death were 3.36%, 5.02% (p Conclusion In patients with AF and DM, risk of stroke/TIA/SEE, MI and major bleeding was confined to insulin-treated DM patients only. These patients also had poorer survival rates vs those without DM and those with non-insulin-treated DM, reinforcing previously published data showing a strong association between insulin treatment and poorer outcomes, and a mild/absent association between non-insulin treatments and poorer outcomes in patients with AF and DM. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): This research was funded by Daiichi Sankyo Europe.

Sodium-glucose cotransporter 2 (SGLT2) inhibitors reduce cardiovascular mortality in patients with and without diabetes mellitus, but underlying mechanisms remain unclear. Autophagy is an important cardioprotective mechanism under acute stress conditions, but excessive autophagy can accelerate myocardial cell death leading to autosis. In this study we evaluated the role of empagliflozin (EMPA) against cardiac injury in streptozotocin (STZ)-induced diabetic mice, and assessed underlying mechanisms. EMPA (10 mg/kg/die)-treated diabetic male mice had a lower number of TUNEL-positive apoptotic cells (%TdT+ 4.9±2, p Funding Acknowledgement Type of funding sources: None.

Background Heart failure (HF) occurs in approximately 26% of patients with atrial fibrillation (AF). Real-world data of oral anticoagulation with edoxaban in AF patients with HF history are limited. Purpose To compare edoxaban effectiveness and safety in AF patients with or without HF history. Methods The Global ETNA-AF programme (EU: NCT02944019, Japan: UMIN000017011, South Korea/Taiwan: NCT02951039) integrates data from multiple prospective, observational, noninterventional regional studies of AF patients receiving edoxaban for stroke prevention. This snapshot analysis summarises baseline characteristics and 2-year annualised rates of all-cause death, cardiovascular (CV) death, stroke (haemorrhagic, ischaemic, any), and bleeding (major bleeding [MB], major gastrointestinal [GI] bleeding, intracranial haemorrhage [ICH], clinically relevant nonmajor bleeding [CRNMB], and any bleeding) in patients with or without HF history. Univariate Cox regression models assessed clinical outcomes. Results Data from 27,333 patients (5258 with HF history) from Europe, Japan, South Korea, and Taiwan were analysed. Patients with HF history were significantly older and had lower mean body weight and creatinine clearance (P Conclusions In AF patients receiving edoxaban, the rates of MB, major GI bleeding, and CV or all-cause death were higher when comparing those with versus without HF history. The higher incidence of MB and major GI bleeding in patients with HF history did not lead to proportionally higher fatal bleeding rates among all-cause deaths. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): Daiichi Sankyo

Background Atrial fibrillation (AF) patients with a history of ischaemic stroke (IS) have a higher risk for recurrent IS events and were largely excluded from the pivotal, randomised, controlled phase 3 trials on oral anticoagulants. Thus, the effectiveness and safety of edoxaban in these patients need to be studied in a real-world setting. Purpose To compare edoxaban real-world effectiveness and safety in AF patients with or without an IS history. Methods The Global ETNA-AF programme (EU: NCT02944019, Japan: UMIN000017011, South Korea/Taiwan: NCT02951039) integrates data from multiple prospective, observational, noninterventional regional studies of AF patients receiving edoxaban for stroke prevention. This snapshot analysis summarises baseline characteristics with medical history and 2-year annualised rates of all-cause death, cardiovascular (CV) death, stroke (haemorrhagic, ischaemic, any), and bleeding (including major bleeding [MB], major gastrointestinal [GI] bleeding, intracranial haemorrhage [ICH], clinically relevant nonmajor bleeding [CRNMB], and any bleeding) in patients with or without IS history. Results Data from 27,333 patients (3215 with prior IS and 24,118 without) from Europe, Japan, South Korea, and Taiwan were analysed. Patients with IS history were significantly older, more likely ≥75 years of age, and had a lower mean body weight and creatinine clearance (P Conclusions Patients with AF who have a history of IS are more likely elderly; have histories of MB, ICH, and TIA; and have high baseline stroke and bleeding risk scores. Patients with IS history receiving edoxaban have a considerably higher likelihood of experiencing IS or TIA, whereas the risk of experiencing any bleeding event (with the exception of ICH) is only modestly higher than in those without IS history. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): Daiichi Sankyo

Background/Introduction Many clinicians estimate the frailty of patients solely using their clinical expertise instead of validated scores. Previous reports show that women are more often perceived as frail than men. It is uncertain whether the same trend is observed in patients with atrial fibrillation (AF) and if the association between perceived frailty and adverse clinical outcomes is affected by sex. Purpose To assess whether sex affects the association between frailty status and adverse clinical outcomes in patients with AF. Methods ETNA-AF-Europe is an ongoing, post-authorisation, prospective cohort study conducted in 825 centres enrolling patients with AF treated with edoxaban in 10 European countries. In this substudy on the first 2-years of follow-up, patients were categorised in four subgroups based on sex and clinician-perceived frailty at baseline. We calculated incidence rates (per 100 patient-years) of the composite endpoint of any stroke or systemic embolic event (SEE), of major bleeding, and of all-cause death for the four subgroups; and determined the unadjusted association between perceived frailty (frail vs non-frail) and each outcome, stratified by sex, using Cox proportional hazards models. To assess for consistency in our findings, we tested the same associations by sex category but using objective risk factors: age (>74 vs Results Information about frailty-status was recorded for 12,254 (93.3%) patients, of whom 8.5% of men and 15.4% of women were perceived as frail by their clinician (p Conclusion In our cohort, differences in the risks of clinical outcomes between those who were perceived as frail and those who were not is more pronounced for men than women. Because we did not observe similar trends in the associations between age or CHA2DS2-VASc score subgroups and clinical outcomes, our results indicate that clinicians perceive the extent of frailty differently in men than in women. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): This research was funded by Daiichi Sankyo Europe.

Background Carotid plaque ulceration has been associated with imaging characteristics of high risk of future events (plaque vulnerability) in patients with a significant degree of stenosis, while little is known about its role in patients with a lesser degree of stenosis and its association with markers of vascular inflammation. Purpose We evaluated the association between imaging characteristics of plaque vulnerability and vascular inflammation detected by different imaging tests. Methods One hundred and seven patients with unilateral asymptomatic carotid artery stenosis (40–60% detected by Doppler ultrasound (DUS)), enrolled in the ongoing Carotid Artery Multimodality Prognostic (CAMP) study were prospectively evaluated with computed tomography angiography (CTA), contrast-enhanced magnetic resonance imaging (CEMRA) and, in a subgroup of patients, with 18-F-fluorodeoxyglucose positron emission tomography (PET). Plaque ulceration was detected by CTA. Variables are expressed as median (1st–3rd quartiles) and number (percentages).The Student's t-test or Mann-Whitney and Chi square or Fisher's exact test were used to study associations among variables. Results An ulcerated plaque was present in 35% patients (n=33) of those undergoing CTA (n=94), while intraplaque hemorrhage and lipid-rich necrotic core were present in 9% and 15% of those undergoing CEMRA. Compared with patients with non-ulcerated plaques, those with an ulcerated plaque had a significant higher degree of stenosis at DUS, a higher target to background ratio (TBR) at 18F-FDG-PET and a higher high-sensitivity cardiac troponin (cTn) T. Conclusions Plaque ulceration is common and associated with higher degree of stenosis, higher indices of wall inflammation and higher serum markers of myocardial injury. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Regione Toscana

Background Atrial fibrillation patients with a history of major bleeding (MB) are at high risk of future bleeding events; this history was an exclusion criterion in pivotal phase 3 trials of anticoagulation for stroke prevention. Real-world edoxaban effectiveness and safety in patients with a history of MB were analysed from the global ETNA programme. Purpose To compare edoxaban effectiveness and safety in AF patients with or without an MB history. Methods The Global ETNA-AF programme (EU: NCT02944019, Japan: UMIN000017011, South Korea/Taiwan: NCT02951039) integrates data from multiple prospective, observational, noninterventional regional studies of AF patients treated with edoxaban for stroke prevention. This snapshot analysis summarises global baseline characteristics and 2-year annualised rates of all-cause death, cardiovascular death, stroke (haemorrhagic, ischaemic, any), and bleeding (including MB, major gastrointestinal bleeding [MGIB], intracranial haemorrhage [ICH], clinically relevant nonmajor bleeding, and any bleeding) in patients with or without MB history. Results Data from 27,333 patients (479 with MB history and 26,854 without) from Europe, Japan, South Korea, and Taiwan were analysed. Patients with MB history were significantly older (P Conclusions Patients with AF receiving edoxaban and who have a history of MB are more likely elderly, male, and have comorbidities, including HF. These patients are also more susceptible to any adverse cardiovascular event. ICH event rates were not higher in patients with prior ICH than those with non-ICH major bleedings, whereas history of MGIB was associated with a high risk of MGIB recurrence. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): Daiichi Sankyo

A 71–year–old woman with chronic lymphocytic leukaemia (CLL) presented to our Cardiology clinic complaining of recent–onset chest pain and dysphonia. Physical examination and ECG were normal. A blood test revealed high levels of high–sensitivity troponin T (373 ng/L) and of C–reactive protein (7 mg/dL); blood counts and differential were normal. Transthoracic echocardiography showed a hyperechogenic appearance of the interatrial septum, the interventricular septum and the right ventricular free wall, as well as a mild circumferential pericardial effusion. Cardiac magnetic resonance imaging revealed multiple intracardiac masses involving both ventricles and the interatrial septum, with evidence of oedema and fibrosis. A chest computed tomography showed the presence of multiple cervical, pulmonary, and mediastinal masses, one of which was biopsied through video–thoracoscopy. At the histological examination, the mass mainly consisted of large pleomorphic peripheral CD10–, CD20+/–, CD79a+, PAX5+, BCL2+, BCL6–, c–MYC+ B cells, with high proliferative activity (Ki–67/MIB1+ 80%). A diagnosis of CLL transformation into diffuse large B–cell lymphoma (DLBCL), also known as Richter’s syndrome (RS), was established (Figure). Despite indication for specific haematological chemotherapy, the patient rapidly deteriorated and died few days after the diagnosis. RS is a rare evolution of CLL and of small lymphocytic lymphoma, affecting 2–8% of such patients (transformation

Background/Introduction ETNA-AF (ETNA) is a multinational, prospective, observational study evaluating the experience with edoxaban in the clinical practice of patients with atrial fibrillation (AF). ENGAGE AF-TIMI 48 was a randomized double-blind trial that tested the clinical benefits of edoxaban versus warfarin. The recommended dose is 60 mg, dose-reduced to 30 mg daily in patients with at least 1 of 3 label-indicated criteria (renal impairment [creatinine clearance: 15–≤50 mL/min], weight ≤60 kg, or concomitant use of potent P-glycoprotein inhibitors). Purpose We assessed whether the effectiveness and safety of edoxaban in clinical practice were consistent with findings from the pivotal randomized clinical trial. Methods We obtained patient-level data from ETNA and ENGAGE AF-TIMI 48. We initially extracted patients from similar geographic regions, and then used propensity-score matching (PSM) to adjust key baseline characteristic differences between studies. The primary effectiveness endpoint was all stroke or systemic embolism (SSE) and mortality; the safety endpoint was major bleeding (MB). We used Cox proportional hazards models to compare event rates for the clinical outcomes between ETNA and ENGAGE AF-TIMI 48. Results 8,615 AF patients with CHADS2 score ≥2 received the 60 mg edoxaban recommended dose (5,462 ETNA; 3,153 ENGAGE AF-TIMI 48). After PSM, key baseline characteristics were well-balanced between the studies: mean age 71.0 years (SD: 9.07); for both ETNA and ENGAGE AF-TIMI 48 median CHA2DS2-VASc score and median HAS-BLED score were 4 and 2. The annualized incidence rate of SSE was 1.65% in ETNA vs 1.53% in ENGAGE AF-TIMI 48 (HR 0.98; 95% CI 0.49, 1.93; p=0.94). ETNA had similar annualized mortality, 2.81%, compared with ENGAGE AF-TIMI 48, 2.34%, (HR 1.49; 95% CI 0.84, 2.63; p=0.17). MB was less frequent in ETNA vs ENGAGE AF-TIMI 48 (1.10% vs 3.56%; HR 0.25; 95% CI 0.14, 0.44; p Conclusions The effectiveness of edoxaban in clinical practice from a large registry was consistent with efficacy findings from the randomized controlled trial. We observed a lower rate of bleeding events in the ETNA observational study compared with the ENGAGE AF-TIMI 48 trial. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): This study was sponsored by Daiichi Sankyo Inc.

Background Ponatinib (PON), a tyrosine kinase inhibitor approved in chronic myeloid leukemia, has proven cardiovascular toxicity. Although sex is a risk factor for PON-induced cardiotoxicity in humans, little is known about its mechanisms in general, and sex-related mechanisms in particular. Objectives To determine the mechanisms of sex-related PON-induced cardiotoxicity and identify potential rescue strategies in a murine model. Methods 24-months-old male and female C57B5 mice were treated with 3 mg/kg/day of PON or vehicle via oral gavage for 28 days, with/without siRNA-Notch1 or siRNA-scrambled via tail vein every 3 days. Results PON + scrambled siRNA-treated male mice had a higher number of TUNEL-positive cells, a higher percentage of senescence-associated β-galactosidase positive senescent cardiac areas, as well as a lower reactivity degree for the survival marker Bmi1 than female counterparts. Proteomics analysis of cardiac tissue showed upstream activation of nitric oxide synthase (NOS) type 2, downstream activation of cell death and production of reactive oxygen species in PON + scrambled siRNA- compared to vehicle or PON + Notch1 siRNA-treated male mice. Upstream analysis showed beta-estradiol activation, while downstream analysis showed activation of cell survival and inhibition of cell death in PON + scrambled siRNA compared to vehicle-treated female mice. PON + scrambled siRNA-treated mice also showed a downregulation of cardiac actin, which was more marked in male; as well as vessel density, which was more marked in female mice. Female hearts showed a greater extent of cardiac fibrosis than male counterparts at baseline, with no significant changes after PON treatment. In contrast, PON + scrambled siRNA-treated mice had less fibrosis than vehicle or PON + Notch1-siRNA-treated mice. Left ventricular systolic dysfunction shown in PON + scrambled siRNA-treated male mice and - to a lesser extent - by female mice was similarly reversed in both PON + Notch1-siRNA-treated male and female mice (Table 1). Conclusions We found a sex-related differential susceptibility and Notch1 modulation in PON-induced cardiotoxicity. This can improve our understanding of sex-related differences and help identify biomarkers in PON cardiotoxicity. Funding Acknowledgement Type of funding sources: None.

Background Vascular calcification and fragility fractures are common age-related disorders, associated with high morbidity and mortality especially in end-stage renal disease. Skeletal disorders occur in dialysis patients. Few studies have provided data on the prevalence of vertebral fractures (VF) and their association with large artery calcifications. Purpose We evaluated the relationship of iliac arteries calcifications (IACs) and abdominal aorta calcifications (AACs) with the risk for VFs in hemodialysis (HD) patients. Methods The VIKI Study is a cross-sectional study involving 387 HD patients from 18 Italian dialysis centers, assessing demographic, clinical and biochemical data in such patients. Biochemical data included bone health markers such as vitamin K levels, vitamin K-dependent proteins, vitamin 25(OH)D, alkaline phosphatase, parathormone, calcium, phosphate, Bone Gla Protein and Matrix Gla Protein. The presence of VF, IACs and AACs were determined through standardized radiograms of the spine. A >20% reduction of vertebral body height was considered a VF. We quantified vascular calcifications by measuring the length of calcium deposits along the abdominal arteries, classifying the degree of severity for the IACs and AACs with a specific score (mild: 0.1–3 cm; moderate: 3.1–5 cm; and severe >5 cm) previously validated for AACs. Results The prevalence of IACs was 56.1%, and of AACs 80.6%. After adjusting for confounding variables, the presence of IACs was associated with 73% higher odds of VF (p=0.028), whereas we found no association (p=0.294) for AACs. The presence of IACs associated with VF irrespective of calcification severity. Patients with IACs had lower levels of the vitamin K2, menaquinone 7 (0.99 vs 1.15 ng/ml; p=0.003), and deficiency of this marker became greater when adjusting for triglyceride levels (0.57 vs 0.87 ng/ml; p Conclusions The presence of IACs, regardless of their extent, appears to be a clinically relevant risk factor for VFs. The association is further enhanced by including vitamin K, a main player in bone and vascular health, in the model. Prospective studies are needed to confirm these findings both in chronic kidney disease patients and in the general population. Funding Acknowledgement Type of funding sources: None.

Background Patients with atrial fibrillation (AF) who initiated vitamin K antagonist (VKA) were at highest risk of stroke and bleeding in the first few months of therapy. Understanding of the temporal trend of clinical events in AF patients on non-VKA oral anticoagulant (NOAC) therapy should aid therapeutic decisions. Purpose To evaluate the temporal trend of clinical events in AF patients receiving edoxaban in routine clinical practice in the Global ETNA-AF program. Methods Global ETNA-AF is a multicentre, prospective, noninterventional program evaluating the safety and effectiveness of edoxaban in patients from European and Asian countries. Thromboembolic, bleeding and death events were analysed separately for the 1st and 2nd year of the follow-up period, using a time-to-first-event estimation of cumulative incidence and annual rate via Kaplan-Meier method. Results A total of 27,617 patients were included in this analysis, 48.6% from Europe and 51.4% from Japan, Korea, and Taiwan. Baseline characteristics were consistent with typical AF population in real world studies (Table 1). Approximately 83% of patients received the recommended edoxaban dose. Annualized rates of ischaemic stroke and major bleeding (ISTH) were lower in the 2nd year than in the 1st year: ischaemic stroke 0.59% (95% CI, 0.50–0.70) vs 0.86% (95% CI, 0.75–0.98), p=0.015; major bleeding 0.87% (95% CI, 0.75–1.00) vs 1.15% (95% CI, 1.02–1.29), p=0.036. The trend toward lower rates of ischaemic stroke and major bleeding in the 2nd year was consistent across regions. All-cause mortality increased slightly from the 1st year to the 2nd year, which was not statistically significant and was not driven by cardiovascular (CV) mortality (Table 2). Conclusion In routine clinical practice in the Global ETNA-AF program, major bleeding and ischaemic stroke rates in >27,000 patients on edoxaban therapy declined from 1st year to 2nd year. Further analyses will investigate whether such trend is influenced by selection for healthier patients over time. Longer follow-up is needed to better understand long-term trends. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): Daiichi Sankyo Table 1. Baseline characteristicsTable 2. Annualised clinical event rates

Background and aim Exercise-induced pulmonary hypertension (Ex-PH), due to impaired pulmonary vascular and right ventricular (RV) contractile reserve on effort, may represent the earliest sign of pulmonary arterial hypertension (PAH), which may develop in Human immunodeficiency virus (HIV) patients with poor disease control. We investigated its association with clinical determinants of immunological status, virological control, and response to antiviral therapy in HIV patients at risk for PAH. Methods In 31 consecutive HIV patients with either low (n=29) or intermediate probability (n=3) of PH at rest, we evaluated the association of isolated ExPH with: time to HIV diagnosis, CD4+ T cell count, clinical progression to AIDS, development of resistance to antiretroviral therapy (ART), HIV RNA levels (copies/mL), time to onset of ART, current use of protease inhibitors, combination of ART with boosters (ritonavir e cobicistat), virological response to ART, ART discontinuation. Isolated ExPH at stress echocardiography (ESE) was defined as absence of PH at rest and systolic pulmonary arterial pressure (sPAP) >45 mmHg or a raise of >20 mmHg during low-intensity exercise (while not exceeding a cardiac output of 10 l/min). Results 20% of the enrolled population developed ExPH. ExPH was inversely associated with CD4+ T cell count (p=0.047), time to HIV diagnosis (p=0.014) and time to onset of ART (p=0.041) compared to patients without ExPH. Patients with ExPH had greater worsening of functional class than patients without ExPH (p Conclusions Isolated ExPH associates with clinical worsening and poorer immunological control in HIV patients. The assessment of ExPH by ESE may help identify subgroups of HIV patients with a propensity to develop subclinical impairment of pulmonary circulation following poor control of HIV infection. Funding Acknowledgement Type of funding sources: None.

Background Cardiac stromal cells (CSCs) contain a pool of cells with supportive and paracrine functions. Various types of mesenchymal stromal cells (MSCs) can influence CSCs in the cardiac niche through their paracrine activity. Ischemia/reperfusion (I/R) leads to cell death and reduction of the paracrine activity of CSCs. The forced coexpression of telomerase reverse transcriptase (TERT) and myocardin (MYOCD), known to potentiate anti-apoptotic, pro-survival and pro-angiogenic activities of MSCs isolated from the adipose tissue (AT-MSCs), may increase CSC survival, favoring their paracrine activities. Aim To investigate the hypothesis that CSCs feature improved resistance to simulated I/R (SI/R) and increased commitment toward the cardiovascular lineage when preconditioned with conditioned media (CM) or extracellular vesicles (EV) released from AT-MSCs overexpressing TERT and MYOCD (T/M AT-MSCs). Methods and results Murine CSCs were isolated with the cardiosphere (CSps) isolation technique. T/M AT-MSCs and their secretome improved spontaneous intracellular calcium changes and ryanodine receptor expression in aged CSps. The cytoprotective effect of AT-MSCs was tested in CSCs subjected to SI/R. SI/R induced cell death as compared to normoxia (28±4 vs 10±3%, p=0.02). Pretreatment with CM (15±2, p=0.02) or with the EV-enriched fraction (10±1%, p=0.02) obtained from mock-transduced AT-MSCs in normoxia reduced cell death after SI/R. The effect was more prononunced with CM (7±1%, p=0.01) or the EV-enriched fraction (2±1%, p=0.01) obtained from T/M AT-MSCs subjected to SI/R. In parallel, we observed lower expression of the apoptosis marker cleaved caspase-3 and higher expression of cardiac and vascular markers eNOS, sarcomeric α-actinin and cardiac actin. Conclusions The T/M AT-MSCs secretome exerts a cytoprotective effect and promotes development of CSCs undergoing SI/R towards a cardiovascular phenotype. Funding Acknowledgement Type of funding sources: None.

Background Non-vitamin K antagonist oral anticoagulants (NOACs) are a preferred treatment option over warfarin for anticoagulation in patients with atrial fibrillation (AF). Management decisions for thromboprophylaxis in AF need to balance the risk of stroke against the risk of bleeding. Various patient characteristics have been identified as independent risk factors for bleeding. A substantial number of bleeding events might be prevented if independent predictors of bleeding were identified. Purpose The present analysis aims at assessing age-adjusted risk predictors of major bleeding during two-year follow-up of unselected European patients with AF in the ETNA-AF-Europe registry. Methods ETNA-AF-Europe is a prospective, multi-centre, post-authorisation, observational study conducted in 825 centres enrolling patients treated with edoxaban once daily in 10 European countries. Wald Chi square tested the association between risk predictors and major bleeding after adjusting for age, given that age is a well-known, strong predictor of anticoagulation-related bleeding in patients with AF. Results Overall, 13,417 patients with AF (edoxaban 60 mg: n=10,248; edoxaban 30 mg: n=3169) completed the two-year follow-up. The mean age was 73.6±9.5 years, with ∼84% of the patients aged over 65 years. Mean CHA2DS2-VASc and HAS-BLED scores were 3.2 and 2.5, respectively. 438 (3.3%) patients had a history of bleeding events at baseline, of which 138 (1.0%) had a history of major bleeding event. Univariate analysis demonstrated that recalculated glomerular filtration rate (Cockcroft-Gault Equation) (GFR-CG) at baseline was the strongest age-adjusted predictor of major bleeding (Wald Chi-Square: 31.84; p Conclusion Bleeding events on therapy with edoxaban can be predicted by quantifying kidney disease and capturing information on heart failure, frailty, prior bleeding, chronic obstructive lung disease and history of myocardial infarction. These data highlight the need for optimal management of anticoagulation therapy and close follow-up of patients with such risk profiles. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): Daiichi Sankyo Europe GmbH Figure 1. GFR-CG as a predictor of major bleedingFigure 2. Predictors of major bleeding

Background Contrast-induced acute kidney injury (CI-AKI) after coronary angiography and percutaneous interventions (PCI) impacts on hospitalization duration and mortality. Pre-procedural hydration is the sole strategy currently recommended for preventing CI-AKI. The role of sodium bicarbonate (SB) although attractive, since urine alkalinization suppresses the production of reactive oxygen species, is still controversial, and the optimal dosing to attain adequate urine alkalinization is still undefined. Purpose The PrevenTion of contrast-inducEd nephropathy with urine alkalinization (TEATE) study was a prospective 3-center 3-arm single-blind randomized controlled trial testing the hypothesis that adequate urine alkalinization is associated with CI-AKI prevention. Secondary endpoints were the efficacy of SB vs saline in achieving adequate urine alkalinization and reducing the incidence of CI-AKI compared with saline. Methods Patients candidate to coronary angiography and/or PCI with moderate-to-severe chronic kidney disease [eGFR of 15 to 60 mL/min/1.73 m2, by the Modification of Diet in Renal Disease Study equation (MDRD)] were randomly assigned to saline hydration (control), oral SB or i.v. SB. The study protocol was registered. We evaluated urinary pH at the time of hospitalization, immediately before coronary angiography and 24–48 hours after angiography. According to urine pH immediately before the procedure, patients were divided in two groups above or below a pH cut-off of 6. Results We enrolled a total of 241 patients: 81 were randomly assigned to the control group, 82 to i.v. SB and 78 to oral SB. Patients achieving a urinary pH >6 before angiography had a lower incidence of CI-AKI (46%) than patients with urinary pH ≤6 (54%) [OR=0.48 (95% CI 0.25–0.9) p=0.023]. The number of patients with urine pH >6 was higher in both the i.v. (71%) and the oral SB (65%) groups compared to the hydration-only group (44%, p=0.004). We found however no difference in the incidence of CI-AKI in the 3 treatment arms (20% in hydration alone, 21% in oral SB group and 22% in iv SB group) (p=0.94). Subgroup analyses according to basal urine pH and eGFR ranges failed to identify statistically significant differences in the development of CI-AKI according to treatment allocation. Conclusions Urinary pH before the administration of contrast medium is an inverse correlate of CI-AKI incidence, and SB is superior to hydration alone in achieving urinary alkalinization. Since, however, SB did not reduce the incidence of CI-AKI, we conclude that urinary pH is a marker and not a mediator of CI-AKI. Funding Acknowledgement Type of funding sources: None.

Background The ESC atrial fibrillation management guidelines recommend a risk-based approach to oral anticoagulant (OAC) therapy. How clinical practice aligns with these recommendations is of interest. Purpose To analyse real world data from Global ETNA-AF program in patient groups stratified by stroke and bleeding risk scores according to ESC guidelines. Methods Global ETNA-AF is a multicentre, prospective, noninterventional program evaluating the safety and effectiveness of edoxaban in patients from European and Asian countries. Baseline characteristics and clinical event data at 2-year follow-up were analysed in 4 subgroups defined by CHA2DS2-VASc score (≥3 for female / ≥2 for male [OAC recommended] vs 2 for female / 1 for male [OAC should be considered]) and HAS-BLED score (≥3 [Bleeding risk high] vs Results Of 27,616 patients included in this analysis, 23,152 (83.8%) were in the “OAC recommended” category and 3,539 (12.8%) were in the “OAC should be considered” category. Only 3.3% of patients did not meet ESC guideline criteria for OAC initiation. Among patients with high bleeding risk, 98% were in the “OAC recommended” category. A similar distribution was observed across regions (Table 2). The recommended edoxaban dose was used in the vast majority (>80%) of patients across all risk stratification subgroups. In the “OAC recommended” category, patients with high bleeding risk had higher rates of thromboembolic, bleeding, and death events than those with low bleeding risk. Conclusion Data from routine clinical practice in Global ETNA-AF demonstrate high concordance of edoxaban treatment with ESC guidelines. Edoxaban dose is consistent with label recommendation in the vast majority (>80%) of patients. Clinical event rates were generally low across all risk groups, including acceptable bleeding rates in anticoagulated patients with high bleeding risk. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): Daiichi Sankyo Table 1. Subgroups as per ESC guidelinesTable 2. Patient characteristics & events

Background Oral anticoagulation is highly effective in preventing ischaemic stroke in patients with atrial fibrillation, but 1–2% of the patients suffer an ischaemic stroke upon anticoagulation. Outcomes are further influenced by various factors, and recent research has focussed on identifying risk factors that could be helpful in predicting stroke outcomes in anticoagulated patients. This could further assist clinicians in timely identification and management of high-risk patients. Purpose The present analysis aims to assess the age-adjusted risk predictors of ischaemic stroke and systemic embolic events (SEE) (including transient ischaemic attack [TIA]) during two-year follow-up of unselected European patients with AF in the ETNA-AF-Europe registry. Methods ETNA-AF-Europe is a prospective, multi-centre, post-authorisation, observational study conducted in 825 centres enrolling patients treated with edoxaban once daily in 10 European countries. Wald Chi square tested the association between risk predictors and stroke and SEE after adjusting for age, given that age is a well-known, strong predictor of stroke. Results A total of 13,417 patients with AF (edoxaban 60 mg: n=10,248; edoxaban 30 mg: n=3169) completed the two-year follow-up. The mean age was 73.6±9.5 years, with ∼84% of the patients aged over 65 years. The mean weight was 81.0±17.3 kg, estimated glomerular filtration rate was 74.4±30.5 ml/min/1.73m2 and males were 56.6%. The mean CHA2DS2-VASc and HAS-BLED scores were 3.2 and 2.5, respectively. Univariate analysis demonstrated that history of TIA at baseline was the strongest age-adjusted predictor of stroke and SEE (Wald Chi-square: 77.69; p Conclusion History of TIA, CHA2DS2-VASc score, history of stroke, frailty and HAS-BLED score are independently associated with an increased age-adjusted risk of ischaemic stroke, TIA and SEE in anticoagulated patients with AF. These findings highlight the importance of optimising anticoagulation therapy in secondary prevention of TIA and in patients with high CHA2DS2-VASc scores, ensuring the correct use of NOACs - adherence and correct dosing - in this high-risk population. These findings also suggest that additional therapies could be needed to prevent stroke in this population. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): Daiichi Sankyo Europe GmbH Figure 1. History of TIA as a predictorFigure 2. CHA2DS2-VASc score as a predictor

Background Whether non-alcoholic fatty liver disease (NAFLD) is a risk factor for cardiovascular (CV) events is still debated. Currently available evidence derives from non-homogeneous studies yielding conflicting results. Purpose We set out to assess the relationship between NAFLD and CV morbidity and mortality by pooling results of previous studies. Methods We performed a systematic review and meta-analysis of prospective observational studies published from 1966 through 2021 reporting summary-level outcome data in subjects with and without NAFLD. Adjusted risk ratios (RRs) and 95% confidence intervals (CIs) for all-cause mortality, CV mortality, myocardial infarction (MI), stroke, major adverse cerebrocardiovascular events (MACCE) and atrial fibrillation (AF) were pooled through inverse variance random-effect meta-analysis to compute the summary effect size. We performed post-hoc subgroup analysis stratified by geographical region and univariate mixed-effect model meta-regression analysis to address statistical heterogeneity. Results We identified a total of 29 studies pooling an overall population of 5,626,573 middle-aged individuals (mean age 56±8; male sex 53%; NAFLD 5.8%, n=326,389). Mean follow-up was 10±6 years. Compared with control population, presence of NAFLD was associated with similar risk of all-cause death (RR 1.17; 95% CI 0.89–1.52) and CV death (RR 0.84; 95% CI 0.64–1.10). When analysed by geographic location, pooled estimates of RR (95% CI) for all-cause death were 1.57 (1.00–2.48) for Western countries, and 0.81 (0.52–1.1.26) for Eastern countries (test for subgroup difference, P=0.04). Meta-regression analysis showed a stronger relationship between NAFLD and all-cause mortality proportional to increasing body mass index (P=0.048). NAFLD was associated with increased risk of myocardial infarction (RR 1.35; 95% CI 1.09–1.68), stroke (RR 1.20; 95% CI 1.06–1.35), MACCE (RR 2.09; 95% CI 1.57–2.78) and atrial fibrillation (RR 1.37; 95% CI 1.05–1.78). Conclusion NAFLD portends excess all-cause mortality but only in Western countries. CV mortality was similar in NAFLD and non-NAFLD groups. NAFLD is associated with increased risk of incident MI, stroke, MACCE and AF. Funding Acknowledgement Type of funding sources: None. Figure 1Figure 2

Background Use of vitamin K antagonists (VKAs) is associated with a crude event rate of 23% per year for worsening renal function (WRF). Although non-vitamin K antagonist oral anticoagulants (NOACs) have been associated with a lower risk of longitudinal decline in renal function compared with VKAs, available evidence on renal function decline in patients using NOACs is still limited. Furthermore, renal function is a dose reduction criterion for NOACs, which poses an important question about how physicians should treat patients whose renal function worsens over time. Purpose To evaluate the degree of renal function decline in AF patients treated with edoxaban after 2 years of follow-up, and to investigate clinical outcomes of patients with vs without WRF in the ETNA-AF-Europe study. Methods ETNA-AF-Europe is a multinational, multicentre, observational, post-authorisation safety study conducted in 825 sites in 10 European countries. Results are based on a data snapshot taken on 26th October 2020 which include data up to 2 years of follow-up. Patients were excluded from the analysis population if data to calculate estimated glomerular filtration rate [eGFR] were not available for at least one of the follow-up time-points of 1-year and 2-year. We categorised patients (n=9084) into two subgroups: 1) those with WRF (i.e. ≥25% decline in eGFR from baseline; n=918), and 2) those without WRF (n=8166). eGFR was estimated using the Cockcroft-Gault formula. Baseline characteristics and annualised event rates including 95% confidence intervals were analysed using descriptive analyses. Results Of the 13,417 patients in ETNA-AF-Europe who were included in the 2-year follow-up analysis, 9084 were included in this subgroup analysis, of whom 56.2% were male. Baseline eGFR were similar between patients with and without WRF when comparing across the different renal function categories (Table 1). The majority of the edoxaban-treated patients did not experience WRF (89.9%) during the 2 years of follow-up. The proportion of patients with WRF (10.1%) were older, more often frail and had higher rates of underlying comorbidities, such as diabetes, hypertension and heart failure (Table 1). Patients with WRF had higher annualised event rates of all-cause and cardiovascular death than those without (3.78% vs 1.90% and 2.06% vs 0.92%, respectively). Major bleeding and stroke rates were low, but numerically higher in patients with renal worsening compared to those without WRF (Figure 1). Intracranial haemorrhage rates remained low (0.17% vs 0.19%; Figure 1) in both subgroups. Conclusions This subgroup analysis provides real-world evidence for a low risk of WRF in AF patients treated with edoxaban over a 2-year period. Patients with WRF had higher mortality than those without, as well as numerically higher major bleeding and stroke rates. Importantly, intracranial haemorrhage rates remained low irrespective of WRF. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): Daiichi Sankyo Europe GmbH /

Funding Acknowledgements Type of funding sources: Public grant(s) – EU funding. Main funding source(s): The EVINCI study was supported by a grant from the European Union FP7-CP-FP506 2007 project (GA 222915). The SMARTool study was supported by a grant from the European Union H2020-PHC-30-2015 (GA 689068). This study was also partially supported by a grant from AMGEN (Protocol N. 20167781, 2017). Background. High triglycerides (TG) and low high-density lipoprotein cholesterol (HDL-C) characterize an atherosclerotic cardiovascular disease (CAD) risk condition defined as atherogenic dyslipidemia. Aim. To assess whether atherogenic dyslipidemia defined by TG/HDL-C ratio predicts CAD related outcomes in patients with stable angina, independently of other risk factors and treatments. Methods. We studied 355 patients (60 ± 9 y, 211m) with stable angina from the EVINCI Outcome study. Patients were characterized for clinical, bio-humoral and imaging profiles, managed clinically, and followed for 4.5 ± 0.9 years. A computed tomography angiography (CTA) coronary risk score was obtained at baseline in all patients, and at follow-up in 154 of them. The primary composite outcome was all-cause mortality and non-fatal myocardial infarction. CTA scan was repeated at follow-up in 154 patients to assess CAD progression. Results. The median value of TG/HDL-C ratio was 2.095 (2.079IQR). At baseline, the proportion of males, smoking, diabetes and metabolic syndrome, as well as circulating bio-markers of abnormal glucose metabolism and myocardial damage progressively increased across quartiles of TG/HDL-C ratio. The CTA score was significantly higher in the IV quartile of the TG/HDL-C ratio and both were the only independent predictors of the primary (CTA Score: HR 1.06, 95%CI 1.03-1.09, p = 0.001; TG/HDL-C IV quartile: HR 2.85, 95%CI 1.30-6.26, p Conclusions. In patients with stable angina, the TG/HDL-C ratio expresses a cardio-metabolic atherogenic disorder which is progressive over time and is associated with CAD related outcomes independently of LDL-C levels and treatments.

Funding Acknowledgements Type of funding sources: Private company. Main funding source(s): Daiichi Sankyo Background Age is a risk factor for ischemic stroke and bleeding in patients with atrial fibrillation (AF). The large dataset from the global prospective, noninterventional ETNA-AF program allows for analysis of the impact of age on clinical events in AF patients treated with edoxaban. Purpose Evaluate the safety and effectiveness of edoxaban by age subgroups and the impact of age on clinical events. Methods Baseline patient characteristics, thromboembolic and bleeding events, and mortality data were collected from patients with 2-year follow-up in ETNA-AF program and analyzed in defined age subgroups. Cox regression analysis was conducted using age as a continuous variable and clinical events as outcome variables. Results A total of 27,617 patients were categorized into four age subgroups: Conclusion Two-year follow-up data from the global ETNA-AF program support the use of edoxaban as a safe and effective treatment for AF patients across all age groups, including the very elderly, in routine clinical care. The impact of age on the risk of ICH was smaller than that of ischemic stroke and major bleeding.

Funding Acknowledgements Type of funding sources: Private company. Main funding source(s): Daiichi Sankyo Europe OnBehalf ETNA-AF-Europe investigators Background Oral anticoagulation (OAC) for stroke prevention is essential in the management of patients with atrial fibrillation (AF). The assessment of OAC use in routine clinical care and the effects of this therapy on outcomes and safety are important. Purpose: We analysed two-year outcome data with adjudicated follow-up results in 13,417 patients with AF treated with edoxaban. Methods: ETNA-AF-Europe (Clinicaltrials.gov: NCT02944019) enrolled 13,417 consecutive patients with AF treated with edoxaban in 825 centres in 10 European countries and 2-year prospectively collected, real world data is presented. Results: Edoxaban was prescribed according to licence recommendations in 83.1% (n = 11,146) of patients (Table). Whilst three quarters of patients were prescribed edoxaban 60 mg (n = 10,248, 76.4%), the quarter prescribed edoxaban 30 mg were older (79.5 versus 71.8 years), had a higher stroke risk (CHA2DS2-VASc score: 3.9 versus 3.0) and a higher bleeding risk (HAS-BLED score: 2.9 versus 2.4). Thromboembolic and bleeding events were more common in patients receiving edoxaban 30 mg OD without differences in intracranial haemorrhage (ICH) (Figure). Patients prescribed a non-recommended dose of edoxaban had a numerically higher stroke risk (CHA2DS2-VASc score: 3.6 versus 3.1) with subsequent higher rates of ischemic stroke and mortality, however they also had higher bleeding rates, with the exception of ICH (table) despite a similar initial bleeding risk (HAS-BLED score: 2.7 versus 2.5). Conclusions: In this large, European data set reporting two-year outcomes on edoxaban therapy, no additional safety signals were observed and event rates were in line with those observed in ETNA-AF after 1 year and in ENGAGE AF-TIMI 48, re-affirming the safety and effectiveness of edoxaban licence recommendations in a real world setting of patients with AF. All key events of interest, other than intracranial haemorrhage, were numerically lower in patients prescribed the licenced recommended dose. Outcomes with rec. vs non-rec. dosesn (%/year [95%CI])Recommended dose (n = 11,146; 83.1%)Non-recommended dose (n = 2271; 16.9%)Any stroke/SEE138 (0.68 [0.57;0.80])31 (0.76 [0.51;1.07])Ischaemic stroke99 (0.48 [0.39;0.59])26 (0.63 [0.41; 0.93])Major bleeding189 (0.93 [0.80;1.07])49 (1.20 [0.89;1.59])Intracranial haemorrhage43 (0.21 [0.15;0.28])7 (0.17 [0.07;0.35])All-cause mortality729 (3.55 [3.30;3.82])208 (5.04 [4.38;5.78])CV mortality405 (1.97 [1.79;2.18])113 (2.74 [2.26;3.30])CI, confidence interval; CV, cardiovascular; rec., recommended; SEE, systemic embolic event.Abstract Figure. Annualised event rates at 2-year FU

Funding Acknowledgements Type of funding sources: Private company. Main funding source(s): Daiichi Sankyo Background and Purpose The large global Edoxaban Treatment in routiNe clinical prActice (ETNA)-AF program was designed to assess the safety and effectiveness of edoxaban, complementing randomized clinical trials. Methods ETNA collects data on patient characteristics and clinical events in unselected AF patients treated with edoxaban for stroke prevention, integrating data from prospective, noninterventional studies conducted in Europe, Japan, South Korea, and Taiwan. Results The 2-year follow-up analysis included 27,617 patients, the majority of whom (82.6%) received the recommended dose according to the local label. At baseline, the mean age was 73.6 ± 9.8 years and 58.1% were male. Half of the patients (50.5%) were 75 years or older. The CHA2DS2-VASc score was 3.3 ± 1.5, and the modified HAS-BLED score was 2.4 ± 1.1. The rate of ischemic stroke was 0.74%/yr, major bleeding 1.02%/yr, intracranial hemorrhage 0.29%/yr, and major gastrointestinal (GI) bleeding 0.51%/yr. All-cause mortality was 3.13%/yr, and cardiovascular (CV) mortality 1.45%/yr (see Table). Conclusion The rates of ischemic stroke and major bleeding events remained low globally and across regions during the two-year follow-up period in AF patients treated with edoxaban. Global(N = 27,617) Japan(N = 11,330) Korea/Taiwan(N = 2,870) Europe(N = 13,417) Age, mean (SD) 73.6 (9.8) 74.2 (10.1) 71.6 (9.5) 73.6 (9.5) Gender, male, % 58.1 59.4 60.2 56.6 Weight [kg], median (IQR) 69 (58, 81) 59 (51, 68) 65 (57, 73) 80 (70, 90) CrCL [mL/min], mean (SD) 68.7 (28.4) 63.9 (25.8) 63.4 (23.7) 74.4 (30.5) CHA2DS2-VASc, mean (SD) 3.3 (1.5) 3.5 (1.7) 3.1 (1.4) 3.2 (1.4) Mod. HAS-BLED≠, mean (SD) 2.4 (1.1) 2.4 (1.1) 2.3 (1.1) 2.5 (1.1) Edoxaban 60mg/30mg, % 53.5 / 46.5 27.6 / 72.4 48.8 / 51.2 76.4 / 23.6 2-year clinical events, N (%/year), [95% CI] Major Bleeding (ISTH) 477 (1.02) [0.93; 1.11] 188 (1.09) [0.94; 1.25] 51 (1.00) [0.74; 1.31] 238 (0.97) [0.85; 1.11] Intracranial Hemorrhage 135 (0.29) [0.24; 0.34] 68 (0.39) [0.30; 0.50] 17 (0.33) [0.19; 0.53] 50 (0.20) [0.15; 0.27] Major GI Bleeding 241 (0.51) [0.45; 0.58] 122 (0.70) [0.58; 0.84] 18 (0.35) [0.21; 0.55] 101 (0.41) [0.33; 0.50] Any Stroke 455 (0.97) [0.88; 1.06] 244 (1.41) [1.24; 1.60] 54 (1.06) [0.80; 1.38] 157 (0.64) [0.54; 0.75] Ischemic Stroke 347 (0.74) [0.66; 0.82] 179 (1.03) [0.89; 1.20] 43 (0.84) [0.61; 1.13] 125 (0.51) [0.42; 0.61] Hemorrhagic Stroke 99 (0.21) [0.17; 0.26] 67 (0.39) [0.30; 0.49] 9 (0.17) [0.08; 0.33] 23 (0.09) [0.06; 0.14] All-cause Death 1479 (3.13) [2.98; 3.30] 470 (2.70) [2.46; 2.96] 72 (1.40) [1.09; 1.76] 937 (3.80) [3.56; 4.05] CV Death 684 (1.45) [1.34; 1.56] 140 (0.80) [0.68; 0.95] 26 (0.50) [0.33; 0.74] 518 (2.10) [1.92; 2.29] ≠Excluding labile INR.

Funding Acknowledgements Type of funding sources: Private company. Main funding source(s): Daiichi Sankyo Europe OnBehalf ETNA-AF-Europe investigators Background Coronary (CAD) and peripheral artery disease (PAD) are common comorbidities in patients with atrial fibrillation (AF). Such concomitant vascular disease may affect the effectiveness and safety of treatment with edoxaban, but data from daily practice are limited. Purpose: To determine the incidence of ischaemic and bleeding events in edoxaban-treated AF patients with CAD/PAD, and to assess whether the effect of edoxaban might be influenced by concomitant vascular disease. Methods: With 1-year follow-up data from ETNA-AF-Europe, clinical characteristics and frequencies of adverse events were compared between AF-patients with and without CAD/PAD. Results: Of 13,089 patients, 2956 had vascular disease (n = 2738; 92.6% had CAD). Patients with CAD/PAD were older, had lower creatinine clearance, higher stroke and bleeding risk scores, and were more frequently prescribed the reduced dose of edoxaban than those without these comorbidities (Table). Rates of stroke/systemic embolism (0.99 vs 0.77%/year), and major bleeding (1.28 vs 0.98%/year) were numerically higher in patients with CAD/PAD than in those without. Myocardial infarction (1.31 vs 0.30%/year), cardiovascular deaths (2.33 vs 1.43%/year) as well as all-cause deaths (5.18 vs 3.01%/year) occurred significantly more often in the CAD/PAD subgroup (Figure). Conclusions: Rates of ischaemic and bleeding events are low in unselected edoxaban-treated AF patients, regardless of the presence/absence of concomitant vascular disease. The higher rates of myocardial infarction and (non-)cardiovascular death in the CAD/PAD subgroup are thought to be largely unrelated to differences in the effect of edoxaban, but attributable to the differences in baseline intrinsic risks instead. Nonetheless, these differences warrant further investigation. Baseline characteristics n (%) or Mean ± SDPatients with CAD and/or PADPatients without CAD and/or PADTotal (N = 2956)Edoxaban 60 mg (n = 2044)Edoxaban 30 mg (n = 915)Total (N = 10,133)Edoxaban 60 mg (n = 7947)Edoxaban 30 (n = 2186)Male2115 (71.5)1541 (75.4)574 (62.7)5315 (52.5)4520 (56.9)795 (36.4)Age, years75.3 ± 8.573.4 ± 8.279.4 ± 7.673.1 ± 9.771.4 ± 9.379.6 ± 8.1Body mass index, kg/m²28.1 ± 4.728.6 ± 4.727.0 ± 4.728.1 ± 5.228.6 ± 5.226.3 ± 5.1eGFR,* mL/min/1.73m²69.3 ± 28.378.2 ± 27.450.7 ± 19.875.7 ± 30.983.2 ± 29.650.1 ± 19.5(calc.)CHA2DS2-VASc3.5 ± 1.43.3 ± 1.44.0 ± 1.43.0 ± 1.42.8 ± 1.33.7 ± 1.2(calc.) mod. HAS-BLED†2.9 ± 1.12.8 ± 1.13.3 ± 1.12.4 ± 1.12.3 ± 1.12.8 ± 1.0Frailty‡391 (13.2)159 (7.8)232 (25.4)1001 (9.9)453 (5.7)548 (25.1)Data are presented as mean ± standard deviation for continuous variables or n (%) for categorical variables. *Glomerular filtration rate (GFR) was estimated by Cockcroft-Gault formula. †Not including labile international normalised ratio. ‡It was left to the physician"s discretion to categorise a patient as frail.Abstract Figure. One-year outcomes

Funding Acknowledgements Type of funding sources: Private company. Main funding source(s): Daiichi Sankyo Europe OnBehalf ETNA-AF-Europe investigators Background Valvular heart disease (VHD) is a common comorbidity in patients with atrial fibrillation (AF); the optimal anticoagulant treatment of such patients remains largely unexplored. Purpose: To evaluate differences in the baseline characteristics and 1-year event profiles of edoxaban-treated AF patients with or without VHD. Methods: ETNA-AF-Europe prospectively enrolled 13,980 patients with AF from 825 centres in 10 European countries. Baseline characteristics and 1-year annualised event rates for edoxaban-treated AF patients with or without VHD were compared using descriptive analyses. VHD was defined as reported by investigator. Results: Of the 13,092 AF patients who completed the 1-year of follow-up, 2,314 patients had VHD and 10,778 did not have VHD at baseline. Patients with VHD were older, had lower body weight and worse renal function, a higher stroke score, and were considered more frail by their physician than patients without VHD (Table). Patients with VHD had higher annualised event rates of all-cause mortality, stroke or systemic embolic events and bleeding events than those without VHD (Figure). However, rates of intracranial haemorrhage and myocardial infarction were similar between those with and without VHD. Conclusions: Patients with or without VHD had low rates of adverse events on receiving edoxaban treatment. Patients with VHD had more comorbidities at baseline and a higher risk of mortality, major bleeding and stroke but not of ICH versus those without VHD after 1 year of treatment. Baseline characteristicsOverall (n = 13,092)Patients with VHD (n = 2314)Patients without VHD (n = 10,778)Male, n (%)7430 (56.8)1245 (53.8)6185 (57.4)Age (years), mean ± SD73.6 ± 9.575.9 ± 8.673.1 ± 9.6Body weight (kg), mean ± SD81.0 ± 17.378.0 ± 15.981.6 ± 17.5CrCl (Cockcroft-Gault) (mL/min), mean ± SD74.3 ± 30.466.0 ± 26.476.0 ± 30.9CHA2DS2-VASc, mean ± SD3.1 ± 1.43.5 ± 1.33.0 ± 1.4Modified HAS-BLED, mean ± SD2.5 ± 1.12.8 ± 1.12.4 ± 1.1Frailty, n (%)1392 (10.6)381 (16.5)1011 (9.4)Current AF type Paroxysmal Persistent Long-standing persistent & permanent7039 (53.9)3159 (24.2)2864 (21.9)1083 (46.9)578 (25.0)648 (28.0)5956 (55.4)2581 (24.0)2216 (20.6)*Frailty was subjectively assessed as perceived by the investigator. AF, atrial fibrillation; CrCl, creatinine clearance; OD, once daily; SD, standard deviation; VHD, valvular heart disease.Abstract Figure. One-year outcomes

Background In AF patients on direct oral anticoagulants (DOAC), safety and effectiveness vary with dose. This might impact treatment decisions. Purpose To investigate the effects of dosing of the DOAC edoxaban in AF patients on safety and effectiveness during 1-year observation in a real-world setting. Methods The Global ETNA-AF NIS included 26,823 patients. Baseline data by edoxaban dosing (60mg/30mg) and their influences on the safety (major bleeding [MB], clinically relevant non-major bleeding [CRNMB]), and effectiveness (stroke, systemic embolism, myocardial infarction [MI], death) were investigated (Table). Results Figure shows the breakdown by dose (60mg vs 30mg) and recommended (rec) vs non-recommended (non-rec) dosing. Patients on non-rec 30mg vs on rec 60mg edoxaban were older (mean ± SD: 74±9 vs 70±9 y); had lower creatinine clearance (72.2±20.6 vs 85.8±26.8 mL/min); and had more comorbidities, history of MB (2.1% vs 1.1%), and strokes (11.0% vs 8.6%). Non-rec 60mg vs rec 30mg patients were younger (75±9 vs 78±9 y), had fewer comorbidities, history of MB (1.2% vs 2.6%), and strokes (10.2% vs 16.4%). In non-rec 30mg vs rec 60mg, MB was not lower and ischaemic events were not higher. In non-rec 60mg vs rec 30mg, no increase in MB, CRNMB or ischaemic events was seen. Conclusion Edoxaban was prescribed at the label recommended dose in the vast majority of patients. Non-rec 30mg patients were sicker than rec 60mg patients while non-rec 60mg patients were less sick than rec 30mg patients. Overall event rates were low, and ischaemic event rates of non-rec 30mg and bleeding event rates of non-rec 60mg were not numerically higher than that of corresponding rec dosing groups. Funding Acknowledgement Type of funding source: Private company. Main funding source(s): Daiichi Sankyo

Background and objectives In atrial fibrillation (AF), assessment of thromboembolic and bleeding risks are recommended to prescribe anticoagulation for stroke prevention. However, AF also increases mortality, and predictors of death are less characterized than predictors for stroke. We investigated the predictive power for mortality of the CHA2DS2-VASc, the HAS-BLED score and their combination. Methods Individual patient data were analyzed from the PREvention oF thromboembolic events-European Registry in Atrial Fibrillation (PREFER AF), a prospective real-world registry with a 12-month follow-up, with a total of 7243 patients enrolled from 461 hospitals and 7 European countries (Austria, France, Germany, Italy, Spain, Switzerland, and United Kingdom). Logistic regression was used to analyze the relationship of the CHA2DS2-VASc and HAS-BLED scores, and their combinations with outcome events, including mortality, at one year. The predictive ability of the scores was analyzed by comparing c-statistics. Results The study sample consisted of 5,209 AF patients with complete information on both scores. Mean age was 71.8±10.46 years; 3145 subjects (60.4%) were male. Events rate of stroke/SEE and major bleeding at one-year were 2.3% (122 patients) and 2.9% (149 patients), respectively. At one year, 3.1% of patients died (160 out of 5,209). Both scores had broadly similar c-statistics; for CHA2DS2-VASc: 0.637, 0.656 and 0.616 for models predicting mortality, SSE and major bleeding, respectively; for HAS-BLED: 0.620, 0.647, and 0.627, respectively. When including the individual components of both scores separately, c-statistics increased to 0.715, 0.694 and 0.636 with CHA2DS2-VASc, and to 0.681, 0.697 and 0.680 with HAS-BLED. The predictive power with both scores combined, removing overlapping components, was higher, with a c-statistic of 0.74, 0.73 and 0.70 for mortality (Table), SSE and major bleeding, respectively. Conclusion Both the CHA2DS2-VASc and the HAS-BLED score predict mortality similarly in AF, and a combination of the score components increases prediction significantly. Such combination may thus be clinically useful. Funding Acknowledgement Type of funding source: None

Background The prevalence of atrial fibrillation (AF) and the need for appropriate anticoagulation increase with age. The benefit/risk profile of direct oral anticoagulants such as edoxaban in elderly population with AF in regular clinical practice is therefore of particular interest. Purpose Analyses of Global ETNA-AF data were performed to report patient characteristics, edoxaban treatment, and 1-year clinical events by age subgroups. Methods Global ETNA-AF is a multicentre, prospective, noninterventional program conducted in Europe, Japan, Korea, Taiwan, and other Asian countries. Demographics, baseline characteristics, and 1-year clinical event data were analysed in four age subgroups. Results Of 26,823 patients included in this analysis, 50.4% were ≥75 years old and 11.6% were ≥85 years. Increase in age was generally associated with lower body weight, lower creatinine clearance, higher CHA2DS2-VASc and HAS-BLED scores, and a higher percentage of patients receiving the reduced dose of 30 mg daily edoxaban. At 1-year, rates of ISTH major bleeding and ischaemic stroke were generally low across all age subgroups. The proportion of intracranial haemorrhage within major bleeding events was similar across age groups. All-cause mortality increased with age more than cardiovascular mortality. Conclusion Data from Global ETNA-AF support the safety and effectiveness of edoxaban in elderly AF patients (including ≥85 years) in routine clinical care with only a small increase in intracranial haemorrhage. The higher all-cause mortality with increasing age is not driven by cardiovascular causes. Funding Acknowledgement Type of funding source: Private company. Main funding source(s): Daiichi Sankyo

Background Clinicians are encouraged to anticoagulate frail and older patients. Both groups were underrepresented in pivotal AF stroke prevention trials. Large, more geographically generalizable data are needed for safety and treatment efficacy in these groups. Aim: ETNA-AF-Europe registry assessed key clinical outcomes and risk scores in frail and older patients compared to their counterparts. Methods ETNA-AF-Europe is a large, prospective, post-authorisation, observational study of patients with AF being prescribed edoxaban. The registry captured frailty as a single, mandatory field as perceived by physicians. Baseline characteristics evaluation and 1-year outcomes of patients were extracted by presence of frailty and age (≥ vs. Results Of, 13,090 enrolled patients, 10.6% were considered frail with coding complete for 12,212 patients. Whilst 27.9% of patients were aged ≥80, of these only 25.3% were frail. Frail patients differed from non-frail and had similar baseline characteristics to those aged ≥80 years. Frail patients were more frequently female, with lower BMI and higher HAS-BLED risk score (Table), and incurred the highest rates of overall and cardiovascular deaths and major bleeding, even more than those aged ≥80 (Figure). Despite this, intracranial haemorrhage (ICH) was surprisingly low and comparable. Conclusions In this large, Europe wide group of patients with AF anticoagulated with edoxaban, patients considered frail by physicians are not always older. A clinical frailty perception is associated with a 4-fold higher short-term mortality. Whilst major bleeding is higher in this frail cohort, ICH is comparably low. The HAS-BLED score in frail patients prescribed edoxaban, appears to predict non-neurological bleeding. These data provide confidence for prescribing edoxaban in frail AF patients to prevent stroke. One-year outcomes Funding Acknowledgement Type of funding source: Private company. Main funding source(s): Daiichi Sankyo Europe GmbH, Munich, Germany

Background Edoxaban is an oral factor Xa inhibitor anticoagulant with 50% renal clearance, and proven efficacy and safety in patients (pts) with atrial fibrillation (AF). The post-authorisation, observational, ETNA-AF-Europe registry (NCT02944019) assessed the risks and benefits of edoxaban in pts with AF from 10 European countries. Purpose Evaluate baseline characteristics and event rates in pts categorised by creatinine clearance (CrCl) at 1-year follow-up of the ETNA-AF-Europe registry. Methods In this analysis, pts were divided into three groups according to CrCl: ≤50 ml/min (I), 50–80 mL/min (II) and ≥80 mL/min (III) (calculated using Cockcroft-Gault). Outcomes were descriptively analysed. Results Pts with the lowest CrCl (Group I) were mostly females, and had a higher mean age, lower body weight, higher stroke and bleeding risk scores and were considered more frail than those with higher CrCl (Groups II and III) (Table). Group I experienced higher rates of stroke or SEE, major or CRNM bleeding, cardiovascular death, and had a higher total mortality (Figure). Rates of intracranial haemorrhage (ICH) and haemorrhagic stroke (intracerebral and subarachnoid haemorrhage) were low and similar in pts across the range of CrCl. Conclusions Those with lower CrCl had more comorbidities and higher event rates than those with higher CrCl, with the exception of ICH and haemorrhagic stroke. A steep rise in the proportion of pts perceived as frail and in overall mortality in the lowest renal function tertile, raises the question whether low renal function is a determinant or a correlate of mortality. Funding Acknowledgement Type of funding source: Private company. Main funding source(s): Daiichi Sankyo Europe GmbH, Munich, Germany

Background Anthracyclines, alone or in combination with other drugs, are among the most effective chemotherapeutic agents to treat breast cancer both in the adjuvant and neoadjuvant settings. Unfortunately, anthracycline-associated dose-dependent cardiotoxicity is a limiting factor in clinical use. Extensive efforts have been devoted to identifying strategies to prevent anthracycline-induced cardiotoxicity. However, most cardioprotective agents have shown little efficacy in clinical trials. We hypothesized that myocardial damage by anthracyclines could be rationally prevented by using trimetazidine (TMZ), previously reported to interfere with anthracycline- and trastuzumab-induced cardiotoxicity. Therefore, we planned a randomized, controlled, open trial to determine whether TMZ may prevent the development of left ventricular (LV) dysfunction in patients receiving standard treatment for breast cancer. Methods The trial included 73 patients (41.2±8.1 years) undergoing surgery for breast cancer, who were scheduled for adjuvant epirubicin-containing chemotherapy and, if indicated, trastuzumab. Patients were randomly allocated in a 1:1 ratio to receive TMZ or baseline therapy only (control group). The main study endpoint was a reduction in the deterioration of left ventricular ejection fraction (LVEF), as evaluated by serial echocardiography performed at randomization and then every 3 months after the start of chemotherapy and for 1 year after its completion. Secondary outcome measures included echocardiographic indices of LV diastolic dysfunction, structural myocardial alterations, as assessed by speckle tracking echocardiography, and changes in cardiac biomarkers (troponin and brain natriuretic peptide). Results We found no significant differences between the two groups regarding baseline clinical and echocardiographic parameters. The two groups reached a similar cumulative dose of doxorubicin. No patient died during the study and no patients withdrew from chemotherapy. Three months after the start of chemotherapy, nonsignificant changes were observed in LVEF, shortening fraction, and LV diameters. No significant changes in cardiac biomarkers were observed in either group. Tissue Doppler imaging detected a significant decrease in myocardial velocities (P=0.001) in the control group, indicating LV diastolic dysfunction. In the same group, speckle tracking imaging revealed a statistically significant alteration in ventricular deformation (P=0.01), which means a decrease in LV systolic function. In the TMZ group, no significant alterations in LV diastolic function were observed. Conclusions Tissue Doppler imaging and speckle tracking imaging are more sensitive than conventional echocardiograms in the early diagnosis of cardiac dysfunction and TMZ seems to have an important role in the prevention of cardiotoxicity. Funding Acknowledgement Type of funding source: None

OnBehalf The ARIC Study Background Age-related left atrial (LA) structural/functional abnormalities in elderly patients with normal sinus rhythm and preserved ejection fraction may precede the development of overt atrial fibrillation, and also may be related to stroke. Purpose To evaluate the association of 3-dimensional echocardiographic (3DE) atrial contractility parameters with subclinical cerebral infarcts (SCIs), as assessed by brain MRI, and clinically diagnosed stroke Methods We studied 407 participants (mean age 76 ± 5 years, 40.5% male) from the Atherosclerosis Risk in Communities Neurocognitive Study (ARIC-NCS) without AF and who underwent a brain MRI and a 3DE examination in 2011-13. We defined 3 groups: those with no cerebral infarcts on brain MRI (NCIs, N = 315); those with MRI-diagnosed SCIs (N = 58); and those with clinically diagnosed stroke (N = 34). Results While still within the normal range, LA indexed volume significantly increased across the 3 groups (P-trend = 0.01).This was accompanied by an increase in the LA global longitudinal strain (GLS), an echocardiographic index of LA reservoir function (P-trend = 0.004). E/e’ divided by LA GLS—index of atrial stiffness—worsened across groups (P-trend = 0.005) and was independently associated with SCIs and Stroke, pooled together, [OR per 1 %-1, 1.97; 95% CI (1.24, 3.11), P = 0.004], and Stroke [OR per 1 %-1, 2.30; 95% CI (1.23, 4.30), P = 0.009]. LA GLS was marginally associated with an increased odd of SCIs [OR per 1 %, 1.07; 95% CI (1.01, 1.13), P = 0.014]. Conclusions Among elderly participants with normal sinus rhythm and preserved ejection fraction in a large cohort study, markers of LA function and stiffness are associated with increased odds of subclinical infarcts and stroke. These data suggest that even subtle LA dysfunction, which may contribute to LA stasis, may predispose to subclinical cerebral infarcts and stroke.

Introduction Edoxaban has been approved for stroke prevention in patients with atrial fibrillation based on its comparable efficacy and superior safety compared to warfarin in the pivotal ENGAGE AF-TIMI 48 trial. ETNA-AF Europe (NCT02944019) was initiated in agreement with the EMA to evaluate benefits and risks of edoxaban treatment in unselected patients in routine clinical practice. Methods 13,980 patients from across 825 hospital and office-based physicians from 10 European countries (Austria, Belgium, Germany, Ireland, Italy, The Netherlands, Portugal, Spain, Switzerland and United Kingdom) were enrolled, and will be followed-up for 4 years. This snapshot analysis includes baseline and first outcome data of 7,672 patients (56.3% of all enrolled patients) that have completed their first 1-year follow-up visit (mean follow-up: 343.5 days). Results The average age of patients was 73.4 years, the mean weight was 81.9 kg (Table 1). Frequent comorbidities include hypertension (77.2%), valvular heart disease (17.4%), congestive heart failure (5.8%) and history of myocardial infarction (4.2%). Patients receiving the 30 mg dose (22.9%) were older, had a lower creatinine clearance and had a higher risk for both stroke and bleeding as compared to those on the 60 mg dose (77.1%). Overall, the incidence of clinical events was low: all-cause mortality: 3.56%/y, major bleeding 0.95%/y, intracranial haemorrhage 0.28%/y, any stroke or systemic embolic events 0.88%/y. Patient characteristics at Year 1 Patient characteristics All patients Edoxaban 60 mg Edoxaban 30 mg [7,672] [5,916 (77.1%)] [1,756 (22.9%)] Age [years] mean (SD) 73.4 (9.26) 71.8 (8.98) 79.1 (7.81) Body weight [kg] mean (SD) 81.9 (17.33) 84.1 (16.80) 74.3 (16.93) CrCl (CG) [mL/min] mean (SD) 75.0 (30.29) 82.5 (29.14) 51.2 (19.75) CHA2DS2-VASc mean (SD) 3.1 (1.38) 2.9 (1.34) 3.8 (1.28) HAS-BLED mean (SD) 2.5 (1.10) 2.4 (1.07) 2.9 (1.08) First occurrence of all-cause mortality (n, %/year) 257 (3.56%) 129 (2.31%) 128 (7.90%) First occurrence of intracranial haemorrhage (n, %/year) 20 (0.28%) 16 (0.29%) 4 (0.25%) First occurrence of major bleeding (n, %/year) 68 (0.95%) 49 (0.88%) 19 (1.18%) First occurrence of stroke/SEE (n, %/year) 63 (0.88%) 45 (0.81%) 18 (1.11%) CG, Cockcroft-Gault; CrCl, creatinine clearance; SD, standard deviation; SEE, systemic embolic events. Conclusions We found low bleeding and stroke rates in 7,672 unselected, mainly elderly AF patients treated with edoxaban in routine clinical practice. These findings were consistent across edoxaban doses and reinforce the effectiveness and safety of NOACs such as edoxaban in routine clinical care in Europe. Acknowledgement/Funding Daiichi Sankyo Europe GmbH, Munich, Germany

Background The benefit of percutaneous mitral valve repair with mitraclip (PMVR) in patients with secondary mitral regurgitation (MR) is still debated. Methods In order to compare the outcome of PMVR with optimal medical therapy (OMT) versus OMT alone in patients with secondary MR, we performed a systematic review and meta-analysis of 2 randomized clinical trials (RCT) and 7 non-randomized observational studies (nROS). Hazard ratios (HR) and 95% confidence intervals (CI) were pooled through inverse variance random-effect model to compute the summary effect size for all-cause mortality, cardiovascular death and cardiac-related hospitalization. Subgroup and meta-regression analysis were also performed. Results An overall population of 3,118 individuals (67% men; mean age, 73 years) was included: 1,775 PMVR+OMT and 1,343 OMT patients, with mean follow-up of 24±15 months. PMVR+OMT was associated with a lower risk of all-cause death (HR: 0.77; 95% CI: 0.68–0.87), cardiovascular death (HR: 0.55; 95% CI: 0.34–0.89) and cardiac-related hospitalization (HR: 0.77; 95% CI: 0.64–0.92). Meta-regression analysis showed that larger left ventricular end-diastolic volume index (LVEDVI) portends higher mortality after PMVR (p Conclusions This study-level meta-analysis shows that PMVR+OMT is associated with reduced all-cause death, cardiovascular death and cardiac-related hospitalization when compared with OMT alone in secondary MR. LVEDVI is a predictive marker of efficacy, as patients with smaller LVEDVI derive the largest benefit from PMVR.

Background The dual antiplatelet therapy (DAPT) duration is a matter of great interest among cardiologists. Because of the conflicting evidences and the necessity to balance the reduction in major cardiac events (MACE) occurrence and the risk of major bleedings after an acute coronary syndrome (ACS), there is a general consensus on prolonging DAPT on an individual basis. There is less consensus on which parameters are to be evaluated. Nowadays tests of platelet reactivity are not included in the decision-making. Few data are available on the prognostic value of aspirin response tests that are sensitive to other mediators of platelet adhesion and aggregation in vivo under flow conditions. Purpose To demonstrate the role of the Platelet Function Analyzer (PFA-100) Collagen/Epinephrine (CEPI) cartridge, which is very sensitive to von Willebrand factor (VWF) levels, an emerging vascular risk factor, in risk stratification in ACS patients undergoing percutaneous coronary intervention (PCI). Methods We measured platelet reactivity by PFA-100 CEPI cartridges in a prospective cohort of 928 patients admitted for ACS between January 2006 to December 2009 and urgently treated by PCI at day 6±1 after admission. All the patients were treated with aspirin and clopidogrel according to current standard of that time. Results High platelet reactivity (HPR) defined as PFA-100 values 190”). At a mean follow up of 5±1 years patients with HPR had a significant increase in cardiac death: 12.3% vs 2.6% (hazard ratio 6.05; 95% confidence interval: 3.34–10.95; p Conclusions Using a multivariable Cox-proportional hazard model, HPR was found to be an independent predictor of MACE. These results indicate that PFA-100 CEPI cartridge, which correlates well with VWF levels, may be a useful point-of-care test to stratify the cardiovascular risk after an ACS. This also underlines the additional value of this test in the decision-making about the correct extension of DAPT.

Background Circulating proprotein convertase subtilisin/kexin type 9 (PCSK9) is a key regulator of LDL cholesterol levels and has emerged as a new therapeutic target in coronary artery disease (CAD). Plasma PCSK9 levels have also been related to other components of the lipid profile associated with atherosclerotic risk. Purpose Aim of the present study was to evaluate the relationship of plasma PCSK9 levels with lipid profile and measures of coronary atherosclerotic burden and risk in patients with stable CAD enrolled in the European EValuation of INtegrated Cardiac Imaging (EVINCI) study. Methods PCSK9 was measured in 412 patients (60.3±8.6 years, 256 males) with symptoms of stable CAD fully characterized by clinical risk factors, bio-humoral profiles, and treatment. All patients underwent coronary computed tomography (CT) angiography to assess the presence and characteristics of coronary atherosclerosis. We calculated an individual CT risk score, expressing the coronary atherosclerotic burden, combining extent, severity, composition, and location of plaques. Results Patients were divided in groups according to PCSK9 quartiles: I (266 ng/mL). LDL and HDL-cholesterol levels were significantly lower while total/HDL-cholesterol ratio was significantly higher in patients in the quartile I than in those in quartile IV (Figure A). CT angiography documented normal vessels in 30 and obstructive CAD in 35% of cases. Compared with patients with the highest levels (quartile IV), patients with the lowest PCSK9 levels (quartile I) had a higher CT risk score, a higher number of mixed plaque and higher hs-cTnI plasma levels (Figure B). PCSK9 itself was not associated with obstructive CAD. At multivariable analysis including clinical variables, medications and lipid variables PCSK9 was an independent predictor of the CT risk score (Coefficient - 0.129 (SE 0.03), p Figure 1 Conclusion PCSK9 levels are independently and inversely associated with the coronary atherosclerotic burden in patients with stable CAD. Acknowledgement/Funding AMGEN grant, EU FP7-CP-FP506 2007 project (grant agreement no. 222915)

Background In patients with non-ischaemic systolic heart failure (HF) and left bundle branch block (LBBB), the systolic phase of the left ventricular (LV) volume/time (V/t) curve at cardiac magnetic resonance (CMR) can display a wide or a narrow pattern (WP/NP). The clinical and prognostic significance of these patterns are currently unknown. Methods Consecutive patients with systolic non-ischaemic HF (LV ejection fraction Results Out of 101 patients (mean age 64±11 years, males 50%), NP was found in 29 and WP in 72, with no difference in QRS duration. Patients with WP had worse clinical presentation and greater LV volumes, but similar LGE prevalence, extent or distribution. The WP subgroup displayed a greater maximal dyssynchrony time, expressed both as absolute duration (192±80 vs. 143±65 ms, P Conclusions In patients with non-ischaemic systolic HF and LBBB, the WP of V/t curves identifies a subgroup of patients with greater LV dyssynchrony, worse clinical conditions and prognosis.

Background As populations age, prevalence of atrial fibrillation (AF) and ensuing need for oral anticoagulation increase. Benefits and risks of nonvitamin K antagonist oral anticoagulants such as edoxaban in the frail, elderly population with AF in regular clinical care is of special interest. Purpose Data from Global ETNA-AF capturing almost 2ehz745.1164 patients treated with edoxaban in Europe, Japan, and Korea/Taiwan, was analyzed to compare outcomes in patients Methods Global ETNA-AF is a multinational, multicentre, prospective, noninterventional program (EU: NCT02944019, Japan: UMINehz745.116417011, Korea/Taiwan: NCT02951039). Demographics, baseline characteristics, and 1-year outcome data were reported for 19416 patients classified into 3 age categories. Results At 1-year follow-up, rates of major bleeding (including intracranial haemorrhage [ICH]) and ischaemic stroke were generally low. All-cause and CV mortality increased with age; CV mortality was a minor proportion of all-cause mortality in all age groups. Rates of major bleeding and ischaemic stroke increased slightly with age, but to a lesser extent than all-cause and CV mortality. There was no increase in the rate of ICH with age. Conclusion Global data from this set of unselected patients support the use of edoxaban as a safe and effective treatment in elderly and very elderly patients with AF in regular clinical care. Acknowledgement/Funding Daiichi Sankyo

Background Studies evaluating the relationship between platelet indices and cardiovascular outcome yielded conflicting results. In particular, the evidence from large, population-based, prospective studies with extended follow-up duration is scarce. Purpose We investigated the incidence of major adverse events in relation to baseline values of platelet count, mean platelet volume (MPV) and platelet distribution width (PDW) in the prospective cohort of the Malmö Diet and Cancer Study. Methods A total of 30,314 middle-aged individuals (mean age 57±8 years; 40% men) were overall included and followed up for a median of 16 years (in total, 468,490 person-years). The following outcome measures were considered: all-cause death, myocardial infarction (MI) and ischemic stroke. Results There was no relationship between increase in MPV or PDW values and adverse events during follow-up. In particular, the incidence of all-cause death, MI and stroke in patients in the 4thquartile of MPV was 19.8% (vs. 20.7% in the 1stquartile; p=0.08), 8.5% (vs. 8.2%; p=0.78) and 7.9% (vs. 7.1%; p=0.09), respectively. The rates of all-cause death, MI and stroke in patients in the 4thquartile of PDW were 20.1% (vs. 20.7% in the 1stquartile; p=0.16), 8.7% (vs. 8.1%; p=0.30) and 8.1% (vs. 7.2%; p=0.09), respectively. There was a significant rise in mortality by platelet count increase (log-rank p264 x 109/L) showed a significantly higher incidence of all-cause death (HR 1.17, 95% CI 1.07–1.28; p=0.001), MI (HR 1.24, 95% CI 1.08–1.43; p=0.003) and stroke (HR 1.20, 95% CI 1.04–1.39; p=0.014) vs the 1stquartile. The higher mortality in the 4thquartile of platelet count was independent of the history of previous stroke, was significant in patients without prior MI (HR 1.18, 95% CI 1.08–1.29; p Conclusions In this population-based, prospective, cohort study there was no difference in the incidence of adverse events across various strata of baseline platelet morphology. However, patients with highest platelet count at baseline showed a significantly higher risk of all-cause death, MI and stroke. Whether or not these individuals should be targeted by more aggressive primary prophylactic measures including antiplatelet treatment, remains to be proven.

Background PCSK9 is a key regulator of serum LDL-cholesterol levels. The relation of PCSK9 with other components of cardiovascular and coronary artery disease (CAD) risk is still debated. Purpose To evaluate the association of PCSK9 plasma levels with cardiovascular and coronary risk profile, in patients with symptoms of suspected stable CAD enrolled in the EVINCI study. Methods PCSK9 was measured in 522 patients (60.4±8.8 years, 318 males) with symptoms of stable CAD Individual risk was characterized by clinical and bio-humoral variables, including lipid/glucose/inflammatory profiles. Obstructive CAD was firstly ruled-in by multimodality non-invasive imaging and, subsequently, assessed by invasive coronary angiography. Results Patients were divided into groups according to PCSK9 quartiles: I (264 ng/mL) (Table). The prevalence of obstructive CAD at invasive angiography and statin treatment did not differ among groups. Compared with patients in quartile IV, patients in quartile I, had a higher prevalence of metabolic syndrome and higher values of body mass index. Among biomarkers, all cholesterol lipoproteins levels progressively increased from quartile I to IV, while insulin and HOMA index values decreased (Table). At multivariable analyses adjusted for medical treatment, the only clinical or bio-humoral variables independently associated with PCSK9 levels were presence of the metabolic syndrome (Coeff. −0.195, SE 0.05, p Table 1 Clinical Variables Quartile I Quartile II–III Quartile IV Biomarkers Quartile I Quartile II–III Quartile IV 264 ng/L 264 ng/L (n=130) (n=261) (n=131) (n=130) (n=261) (n=131) Age, years 61±9 60±9 61±8 Glucose, mg/dL 110±30 117±41 109±29 Male gender 86 (66) 161 (62) 71 (55) Insulin, mUI/mL 13.3±12.5* 11.3±10.1 10.3±10.1 Family history 38 (29)# 86 (33) 58 (44) HOMA index 3.9±4.5* 3.5±4.1 2.9±3.3 Hypertension 78 (60) 164 (63) 88 (67) Tryglicerides, mg/dL 128±86 128±87 118±68 Hypercholesterolemia 72 (55) 158 (61) 81 (62) Total cholesterol, mg/dL 171±43* 181±45 203±55 Diabetes mellitus 43 (33) 91 (35) 37 (28) LDL, mg/dL 99±36* 104±38 119±45 Metabolic Syndrome 45 (35)# 72 (28) 19 (15) HDL, mg/dL 46±13* 52±15 61±19 BMI, kg/m2 28.02±4.00* 28.03±4.25 26.95±4.56 Total/HDL cholesterol 3.8±1.2* 3.7±1.2 3.5±1.1 Significant CAD at ICA 18 (14) 46 (18) 24 (18) hs-CRP, mg/dL 0.41±0.61 0.39±1.38 0.41±0.83 Statins treatment 68 (52) 143 (55) 58 (44) Interleukin 6, ng/L 1.60±2.75 1.30±2.49 1.30±1.68 Chi square test: #p Conclusion In patients with stable CAD, low plasma levels of PCSK9 are associated with the prevalence of metabolic syndrome and its individual components, including, in particular, HDL cholesterol. Acknowledgement/Funding AMGEN grant, EU FP7-CP-FP506 2007 project (grant agreement no. 222915)

Background Non-vitamin K antagonist (VKA) oral anticoagulants (NOACs) have substantially improved anticoagulation therapy for prevention of stroke and systemic embolism in patients with atrial fibrillation (AF), and available routine care data have so far broadly confirmed the safety of different NOACs in routine practice. However, such data for edoxaban are scarce, especially in extremely low and high body weight (BW). These extreme BWs may affect the bioavailability, distribution, and half-life of NOACs and, consequently, outcomes of treatment. Methods We analysed outcomes in normal-weight (BMI 18.5–25) vs overweight (BMI 25–30) and obese (BMI >30) patients enrolled into the ETNA-AF-Europe observational study (NCT02944019) collecting information on patients treated with edoxaban in 825 sites in 10 European countries. This snapshot analysis set includes data of 7,672 patients (56.3% of all enrolled patients) which have completed their 1-year follow-up visit (mean follow-up: 343.5 days). Results Median patient age was 74 years for all patients, 76 years for patients with a BMI 18.5–25 (group 1), 75 years for patients with BMI 25–30 (group 2), and 72 for patients with a BMI >30 (group 3). CrCl was 64 mL/min for patients with a BMI 18.5–25, 68 mL/min for patients with BMI 25–30, and 72 mL/min for patients with a BMI >30. The CHA2DS2-VASc (mean 3.1±1.38) and HAS-BLED (mean 2.5±1.10) score did not differ significantly between groups. As expected, diabetes and hypertension were significantly less prevalent in leaner patients and - accordingly - inversely correlated to age. There was no correlation between body weight and life-threatening bleeding (group 1: 0.28%; group 2: 0.40%; group 3: 0.14%). Also, stroke rates (group 1: 0.74%; group 2: 0.81%; group 3: 0.76%) did not differ between groups. Conclusion BMI, within the range here assessed, does not affect 1-year outcomes in European AF patients treated with edoxaban. Acknowledgement/Funding Daiichi Sankyo Europe GmbH, Munich, Germany

Background In ARISTOTLE, patients with atrial fibrillation and ≥2 dose-reduction criteria [age ≥80 years, weight ≤60 kg, and creatinine ≥1.5 mg/dL (133 μmol/L)] were randomized to apixaban 2.5 mg twice daily (b.i.d) or warfarin. Purpose To determine whether the apixaban dose adjustment in ARISTOTLE resulted in similar efficacy and safety compared to warfarin. Methods The effects of apixaban 2.5 mg b.i.d versus warfarin on stroke or systemic embolism, major bleeding and death in ARISTOTLE patients with ≥2 dose-reduction criteria were compared with the effects of apixaban 5 mg b.i.d in patients with 0 or 1 dose-reduction criterion. Results Of 751 (4.1%) patients with ≥2 dose-reduction criteria, 386 were assigned to apixaban 2.5 mg b.i.d and 365 to warfarin. Compared to patients with 0 or 1 dose reduction criteria (n=17,322), these patients had a higher risks of stroke/systemic embolism (HR =1.78; 95% CI [1.24–2.57]), major bleeding (HR =1.73; 95% CI [1.28–2.32]) and death (HR=3.21; 95% CI [2.69–3.83]), irrespective of whether they were assigned to apixaban or warfarin. The benefits of apixaban 2.5 mg b.i.d compared with warfarin on stroke or systemic embolism, major bleeding, and death in patients with ≥2 dose-reduction criteria were consistent with that of apixaban 5 mg b.i.d in patients with either 0 or 1 dose-reduction criteria (Figure). Conclusions While they are at higher overall risk, patients with appropriate dose reduction criteria have consistent benefits with apixaban 2.5 mg b.i.d. over warfarin. Additional analyses investigating the relationship between apixaban dose and both apixaban plasma concentrations and levels of thrombosis biomarkers are underway. Acknowledgement/Funding Bristol-Myers Squibb and Pfizer, Inc.

Background Edoxaban, a direct FXa inhibitor, has been proven non-inferior in efficacy and safer compared to warfarin in the ENGAGE AF-TIMI 48 trial. In routine care, the safety of edoxaban has not been formally established. ETNA-AF-Europe is a multinational, multi-centre, post-authorisation, observational study (NCT02944019) conducted in 825 sites in 10 European countries. Here 13,980 edoxaban-treated patients with AF were enrolled between November 2016 and February 2018, and will be followed-up for 4 years. Methods 7,672 patients (73.4±9.26 years, 57.5% male) enrolled in the ETNA-AF Europe registry completed the one-year follow-up and were stratified into low-, intermediate- and high-risk for stroke and bleeding using the CHA2DS2-VASc and HASBLED score, respectively. We here analysed the occurrence of stroke, bleeding, intracranial haemorrhage and mortality in such categories. Results The mean CHA2DS2-VASc score at baseline was 3.1±1.38 and the mean HAS-BLED score was 2.5±1.1. Not surprisingly, patients at higher risk were older, had a lower body weight, more comorbidities, and a lower creatinine clearance. A higher proportion of patients at high risk received the reduced 30 mg edoxaban dose. Overall, the yearly event rates of stroke, intracranial haemorrhage, major bleeding and death were low. However, these rates increased consistently in patients with higher stroke and bleeding risks. Residual stroke risk on anticoagulation was comparable to the risk of major bleeding (Table 1). Outcomes by stroke and bleeding risk CHA2DS2-VASc: mean 3.1±1.38 HAS-BLED: mean 2.5±1.1 All patients Low risk (0, 1 if female) Intermediate risk (1, 2 if female) High risk (≥2, 3 if female) Low risk (0, 1) Intermediate risk (2, 3) High risk (≥4) Patients, N 233 1,133 6,304 1,224 4,932 1,516 7,672 First occurrence of outcomes, n (%/year) All-cause mortality 2 (0.92%) 12 (1.11%) 242 (4.09%) 14 (1.21%) 161 (3.47%) 82 (5.78%) 257 (3.56%) Intracranial haemorrhage 0 (0.00%) 1 (0.09%) 19 (0.32%) 2 (0.17%) 10 (0.22%) 8 (0.56%) 20 (0.28%) Major bleeding 0 (0.00%) 6 (0.56%) 62 (1.05%) 2 (0.17%) 43 (0.93%) 23 (1.63%) 68 (0.95%) Stroke/SEE 0 (0.00%) 4 (0.37%) 59 (1.00%) 3 (0.26%) 41 (0.89%) 19 (1.34%) 63 (0.88%) SEE, systemic embolic event. Conclusions In this unselected cohort of patients with AF anticoagulated with edoxaban, high CHA2DS2-VASc and HAS-BLED scores were associated with higher risks of stroke, bleeding and death. Indirectly compared with the expected rates in non-anticoagulated patients, our data underpin the value of anticoagulants such as edoxaban in patients at high risk of stroke and bleeding. Acknowledgement/Funding The ETNA-AF Registry was funded by Daiichi Sankyo Europe GmbH, Munich, Germany.