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Abstract  Isolated noncompaction of the left ventricular myocardium (INVM), first described in 1984, is an unclassified cardiomyopathy and is assumed to occur as an arrest of the compaction process during the normal development of the heart. Between weeks 5 to 8 of human fetal development, the ventricular myocardium undergoes gradual compaction with transformation of the relatively large intertrabecular spaces into capillaries while the residual spaces within the trabecular meshwork gradually flatten or disappear. In the case of INVM, the spaces within the intertrabecular meshwork persist while no other cardiac abnormalities exist. Although there is substantial evidence supporting the developmental hypothesis, other pathogenetic processes responsible for INVM have been discussed. It can be assumed that INVM will be better understood in the future as the molecular genetic basis of cardiomyopathies will be further unravelled. Echocardiography has been shown to be the method of choice in diagnosis of INVM. The diagnostic criteria can be summarized as: 1) appearance of at least four prominent trabeculations and deep intertrabecular recesses; 2) appearance of blood flow from the ventricular cavity into the intertrabecular recesses as visualized by color Doppler imaging; 3) the segments of noncompacted myocardium mainly involve the apex and the inferior mid and lateral mid of the left ventricular wall and typically show a two-layered structure with an endsystolic ratio greater than two between the noncompacted subendocardial layer and the compacted subepicardial layer; 4) absence of coexisting cardiac abnormalities. Magnetic resonance imaging using modern gradient echo sequences has also been shown to diagnose INVM accurately. The clinical presentation of INVM is characterized by a high prevalence of heart failure, thromboembolic events and arrhythmias including ventricular tachycardia and atrial fibrillation. The establishment of a registry, which was initiated by the "Arbeitsgemeinschaft Leitende Kardiologische Krankenhausrzte (ALKK)" recently, may provide further clues for diagnosis, risk stratification, and management of this disease. [ABSTRACT FROM AUTHOR]

Summary Sudden cardiac death (SCD) especially in young otherwise healthy individuals is a devastating situation. In the last decade molecular cardiology has become an important tool in understanding the etiology, pathogenesis and development of familial cardiovascular diseases associated with SCD. Due to the genetic heterogeneity of the diseases, other new genes wait to be discovered. For long QT syndrome (LQTS) and hypertrophic cardiomyopathy (HCM) genotype-phenotype correlation with several hundreds of patients were performed and at least for these two entities the genetic information should be taken into account when risk stratification is performed. For the Brugada syndrome and the catecholaminergic polymorphic ventricular tachycardia (CPVT), a genetic background is proven and both diseases go along with a high incidence of SCD. In terms of risk stratification the significance of an identified SCN5A mutation in a Brugada patient is still a matter of debate. Due to the extraordinary clinical and genetic heterogeneity of arrhythmogenic right ventricular cardiomyopathy (ARVCM) and dilated cardiomyopathy (DCM), large scale investigations on genotyped patients are still lacking. Apart from already known genes/mutations with a malignant phenotype and an increased risk of SCD (ryanodine receptor 2 in ARVC-2 and CPVT; troponin T in DCM and HCM) genetic data does not yet contribute to further therapeutic decisions. ?Silent? gene carriers display a very mild phenotype and could be identified through genetic investigation. These patients would be unexpectedly at risk for generating affected offspring by a 50% chance in an autosomal-dominant transmitted disease and perhaps also of developing malignant arrhythmias if exposed to either cardiac or non-cardiac drugs in case of LQTS. Avoidance of trigger factors may protect these individuals from life threatening arrhythmias and the risk for SCD. [ABSTRACT FROM AUTHOR]

Summary Sudden cardiac death is an important cause of death in developed countries. The majority of sudden cardiac deaths are caused by ventricular fibrillation or by hemodynamically non-tolerated ventricular tachycardias. Genetic alterations contribute to the occurrence of sudden arrhythmic death. Mutations in cardiac ion channels, proteins of the contractile apparatus, cytosceletal proteins or proteins of the sarcoplasmic reticulum can cause inherited arrhythmogenic diseases. Adaptive changes in gene expression or function, e. g., in response to cardiac hypertrophy and heart failure, can also predispose to arrhythmias. Some of the adaptive gene expression changes provoke arrhythmia mechanisms similar to the molecular mechanisms of arrhythmias in inherited arrhythmogenic diseases. [ABSTRACT FROM AUTHOR]

Summary. We report of long-term follow-up of a combined fusiform aneurysm of the right subclavian artery extending to the thyreocervical trunk (3.2×2.8×2,2cm (width×height ×depth)) in a 33-year old patient. As a newborn, the clinical diagnosis of an aortic isthmus stenosis was made without need for intervention at this stage. Further development of the child remained unremarkable until the age of eleven years when he experienced dizziness after sporting activities. Due to clinically proven progress, cardiac catheterization was performed and confirmed the initial diagnosis of a juxtaductale stenosis of the aortic isthmus, which was operated thereafter with an end-to-end anastomosis. Furthermore, an aneurysm of the right subclavian artery was revealed. Since then, non-invasive routine follow-up showed no significant worsening of this aneurysm, which extends to the thyreocervical trunk. The patient has been event free and completely asymptomatic. This case report illustrates the more than twenty years of follow-up of an asymptomatic combined fusiform aneurysm of the subclavian artery and thyreocervical trunk and provides a review of the literature on this topic. Zusammenfassung Wir berichten über den Langzeitverlauf eines kombinierten fusiformen Aneurysmas der Arteria subclavia dexter sowie des Abgangs des Truncus thyreocervicalis (3,2×2,8×2,2cm (Breite×Höhe×Tiefe)) bei einem 33-jährigen Patienten. Bereits perinatal wurde der klinische Verdacht auf das Vorliegen einer Aortenisthmusstenose geäußert, allerdings zum damaligen Zeitpunkt kein Interventionsbedarf gesehen. Die weitere Entwicklung des Kindes verlief zunächst normal, bis im Alter von 11 Jahren der Patient erneut aufgrund nach sportlicher Aktivität verspürten Schwindelgefühls kardiologisch vorgestellt wurde. Bei klinisch evidenter Progression wurde eine Herzkatheterdiagnostik durchgeführt, die eine juxtaductale Aortenisthmusstenose zeigte. Diese wurde konsekutiv mittels End-zu-End-Anastomose 1981 operativ korrigiert. Daneben zeigte sich bereits eine aneurysmatisch veränderte Arteria subclavia dexter, wobei diesbezüglich ein konservatives Procedere vorgeschlagen wurde. Der Patient stellte sich in regelmäßigen Abständen zu einer Verlaufskontrolle in unserer Ambulanz vor und ist seitdem vollständig asymptomatisch. Der vorliegende Bericht zeigt den nunmehr über 20-jährigen asymptomatischen Verlauf eines fusiformen Aneurysmas der Arteria subclavia dexter unter Einbeziehung des ebenfalls fusiform aneurysmatisch veränderten Abgang des Truncus thyreocervicalis und bietet einen Überblick der Literatur zu diesem Thema. [ABSTRACT FROM AUTHOR]

The HAWAI registry evaluated the role of heart rate variability in predicting the occurrence of ventricular tachycardia and fibrillation (VT/VF) and sinus tachycardia in patients with an implantable cardioverter-defibrillator (45 patients with 155 RR recordings). A significant decrease of the mean value of all RR intervals (MeanNN) was observed in the period starting 20 and 40 min prior to VT/VF and sinus tachycardia, respectively. The standard deviation of RR intervals (SDNN) and the power at low frequency (LF) were the only parameters with significant changes prior to VT/VF. For sinus tachycardia, the root mean square of successive differences of all successive RR intervals (r-MSSD) and the power at low and high frequency (HF) decreased, whereas SDNN and the power at very low frequency increased. Comparison of RR recordings preceding VT/VF and sinus tachycardia revealed significant differences of the MeanNN, SDNN, r-MSSD, LF and HF. Based on a classification and regression tree analysis, MeanNN, SDNN and r-MSSD showed a sensitivity of 94.4% and a specificity of 50.6% as predictors of VT/VF. Our results suggest that the temporal changes in heart rate before an arrhythmic event can be used to predict the occurrence of VT/VF. These parameters may be used to optimize pacing therapies designed to prevent VT/VF recurrences as well as for improving device-based discriminators for VT/VF and sinus tachycardia. [ABSTRACT FROM AUTHOR]

Background: Vitamin-K antagonists (VKAs) have widely been replaced by non-VKA oral anticoagulants (NOACs). This includes Austria, Germany and Switzerland, where as VKA, instead of warfarin, the much longer-acting phenprocoumon is used, which was not compared to NOACs in clinical trials., Methods: Using administrative data from a large German health insurance, we included all anticoagulation-naïve patients with a first prescription of a NOAC or VKA between 2012 and 2020. We analysed overall survival, major adverse cardiac and cerebrovascular events, major thromboembolic events and major bleeding., Results: Overall, 570,137 patients were included (apixaban: 26.9%, dabigatran: 4.6%, edoxaban: 8.8%, rivaroxaban: 39.1% and VKA: 20.7% of these 99.4% phenprocoumon). In the primary analysis using a 1:1 propensity score matching-cohort (PSM-cohort), a significantly higher overall mortality was found for apixaban, edoxaban and rivaroxaban (all p < 0.001) but not for dabigatran (p = 0.13) compared to VKA. In this PSM-cohort, 5-year mortality was 22.7% for apixaban versus 12.7% for VKA, 19.5% for edoxaban versus 11.4% for VKA, 16.0% for rivaroxaban versus 12.3% for VKA (all p < 0.001) and 13.0% for dabigatran versus 12.8% for VKA (p = 0.06). The observed effect was confirmed in sensitivity analyses using un-weighted and three different weighted Fine-Gray regression models on the basis of the entire cohort., Conclusions: In this large real-world analysis, apixaban, edoxaban and rivaroxaban, but not dabigatran, were associated with worse survival compared to VKA. These findings, consistent with a few other studies including phenprocoumon, cast profound doubts on the unreflected, general use of NOACs. Randomized trials should assess whether phenprocoumon might actually be superior to NOACs., (© 2024 BARMER Institut für Gesundheitssystemforschung and The Author(s). Journal of Internal Medicine published by John Wiley & Sons Ltd on behalf of Association for Publication of The Journal of Internal Medicine.)

Background and Aims: In patients with atrial fibrillation (AF), recurrent AF and sinus rhythm during follow-up are determined by interactions between cardiovascular disease processes and rhythm-control therapy. Predictors of attaining sinus rhythm at follow-up are not well known., Methods: To quantify the interaction between cardiovascular disease processes and rhythm outcomes, 14 biomarkers reflecting AF-related cardiovascular disease processes in 1586 patients in the EAST-AFNET 4 biomolecule study (71 years old, 46% women) were quantified at baseline. Mixed logistic regression models including clinical features were constructed for each biomarker. Biomarkers were interrogated for interaction with early rhythm control. Outcome was sinus rhythm at 12 months. Results were validated at 24 months and in external datasets., Results: Higher baseline concentrations of three biomarkers were independently associated with a lower chance of sinus rhythm at 12 months: angiopoietin 2 (ANGPT2) (odds ratio [OR] 0.76 [95% confidence interval 0.65-0.89], p=0.001), bone morphogenetic protein 10 (BMP10) (OR 0.83 [0.71-0.97], p=0.017) and N-terminal pro-B-type natriuretic peptide (NT-proBNP) (OR 0.73 [0.60-0.88], p=0.001). Analysis of rhythm at 24 months confirmed the results. Early rhythm control interacted with the predictive potential of NT-proBNP (pinteraction=0.033). The predictive effect of NT-proBNP was reduced in patients randomized to early rhythm control (usual care: OR 0.64 [0.51-0.80], p<0.001; early rhythm control: OR 0.90 [0.69-1.18], p=0.453). External validation confirmed that low concentrations of ANGPT2, BMP10 and NT-proBNP predict sinus rhythm during follow-up., Conclusions: Low concentrations of ANGPT2, BMP10 and NT-proBNP identify patients with AF who are likely to attain sinus rhythm during follow-up. The predictive ability of NT-proBNP is attenuated in patients receiving rhythm control., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Aims: Atrial fibrillation (AF) and concomitant cardiometabolic disease processes interact and combine to lead to adverse events, such as stroke, heart failure, myocardial infarction, and cardiovascular death. Circulating biomolecules provide quantifiable proxies for cardiometabolic disease processes. The aim of this study was to test whether biomolecule combinations can define phenotypes in patients with AF., Methods and Results: This pre-specified analysis of the EAST-AFNET 4 biomolecule study assigned patients to clusters using polytomous variable latent-class analysis based on baseline concentrations of 13 precisely quantified biomolecules potentially reflecting ageing, cardiac fibrosis, metabolic dysfunction, oxidative stress, cardiac load, endothelial dysfunction, and inflammation. In each cluster, rates of cardiovascular death, stroke, or hospitalization for heart failure or acute coronary syndrome, the primary outcome of EAST-AFNET 4, were calculated and compared between clusters over median 5.1 years follow-up. Findings were independently validated in a prospective cohort of 748 patients with AF (BBC-AF; median follow-up 2.9 years).Unsupervised biomolecule analysis assigned 1586 patients (71 years old, 46% women) into four clusters. The highest risk cluster was dominated by elevated bone morphogenetic protein 10, insulin-like growth factor-binding protein 7, N-terminal pro-B-type natriuretic peptide, angiopoietin 2, and growth differentiation factor 15. Patients in the lowest risk cluster showed low concentrations of these biomolecules. Two intermediate-risk clusters differed by high or low concentrations of C-reactive protein, interleukin-6, and D-dimer. Patients in the highest risk cluster had a five-fold higher cardiovascular event rate than patients in the low-risk cluster. Early rhythm control was effective across clusters (Pinteraction = 0.63). Sensitivity analyses and external validation in BBC-AF replicated clusters and risk gradients., Conclusion: Biomolecule concentrations identify cardiometabolic subphenotypes in patients with AF at high and low cardiovascular risk., Competing Interests: Conflict of interest: W.C. is now an employee of ICF (www.icf.com). Both W.C. and V.R.C. performed the work described here while employed by the University of Birmingham. A.J.C. receives personal funds from Acesion, Incarda, Menarini, Milestone, Sanofi, Bayer, Anthos, Daiichi Sankyo, Pfizer, Abbott, Biosense Webster, Biotronik, Boston Scientific, Medtronic, and Johnson & Johnson. P.T.E. receives sponsored research support from Bayer AG, IBM Research, Bristol Myers Squibb, Pfizer, and Novo Nordisk; P.T.E. has also served on advisory boards or consulted for Bayer AG. H.J.G.M.C. discloses advisory board fees from InCarda Therapeutics, Roche Diagnostics, Daiichi Sankyo, Sanofi, Acesion, and Atricure. Speaker fee from Medtronic. U.S. received consultancy fees or honoraria from Università della Svizzera Italiana (USI, Switzerland) and Roche Diagnostics (Switzerland). U.S. was supported by a grant from EP Solutions Inc. (Switzerland) and is co-founder and shareholder of YourRhythmics BV, a spin-off company of the University of Maastricht. C.M. has received speaker fees from AstraZeneca, Novartis, Boehringer Ingelheim/Lilly, Bayer, Pfizer, Sanofi, Aventis, Apontis, and Abbott outside of this work. C.M. has participated in advisory boards for Boehringer Ingelheim and Novo Nordisk. R.B.S. has received lecture fees and advisory board fees from BMS/Pfizer and Bayer outside of this work. L.F. received institutional research grants by EU 633196 (CATCH-ME) and EU 965286 (MAESTRIA). British Heart Foundation (AA/18/2/34218), German Center for Cardiovascular Research, supported by the German Ministry of Education and Research (DZHK), and several biomedical companies active in the field of research. L.F. is listed as inventor on two issued patents held by the employing institution (Atrial Fibrillation Therapy WO 2015140571, Markers for Atrial Fibrillation WO 2016012783). P.K. received research support for basic, translational, and clinical research projects from the European Union, British Heart Foundation, Leducq Foundation, Medical Research Council (UK), and German Center for Cardiovascular Research, from several drug and device companies active in AF, and has received honoraria from several such companies in the past, but not in the last 3 years. P.K. is listed as an inventor on two issued patents held by the institution (Atrial Fibrillation Therapy WO 2015140571, Markers for Atrial Fibrillation WO 2016012783)., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Background: Days alive out of hospital (DAOH) is an objective and patient-centered net benefit end point. There are no assessments of DAOH in clinical trials of interventions for atrial fibrillation (AF), and it is not known whether this end point is of clinical utility in these populations., Methods and Results: ROCKET AF (Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation) was an international double-blind, double-dummy randomized clinical trial that compared rivaroxaban with warfarin in patients with atrial fibrillation at increased risk for stroke. We assessed DAOH using investigator-reported event data for up to 12 months after randomization in ROCKET AF. We assessed DAOH overall, by treatment group, and by subgroup, including age, sex, and comorbidities, using Poisson regression. The mean±SD number of days dead was 7.3±41.2, days hospitalized was 1.2±7.2, and mean DAOH was 350.7±56.2, with notable left skew. Patients with comorbidities had fewer DAOH overall. There were no differences in DAOH by treatment arm, with mean DAOH of 350.6±56.5 for those randomized to rivaroxaban and 350.7±55.8 for those randomized to warfarin ( P =0.86). A sensitivity analysis found no difference in DAOH not disabled with rivaroxaban versus warfarin (DAOH not disabled, 349.2±59.5 days and 349.1 days±59.3 days, respectively, P =0.88)., Conclusions: DAOH did not identify a treatment difference between patients randomized to rivaroxaban versus warfarin. This may be driven in part by the low overall event rates in atrial fibrillation anticoagulation trials, which leads to substantial left skew in measures of DAOH.

Aims: Clinical concerns exist about the potential proarrhythmic effects of the sodium channel blockers (SCBs) flecainide and propafenone in patients with cardiovascular disease. Sodium channel blockers were used to deliver early rhythm control (ERC) therapy in EAST-AFNET 4., Methods and Results: We analysed the primary safety outcome (death, stroke, or serious adverse events related to rhythm control therapy) and primary efficacy outcome (cardiovascular death, stroke, and hospitalization for worsening of heart failure (HF) or acute coronary syndrome) during SCB intake for patients with ERC (n = 1395) in EAST-AFNET 4. The protocol discouraged flecainide and propafenone in patients with reduced left ventricular ejection fraction and suggested stopping therapy upon QRS prolongation >25% on therapy. Flecainide or propafenone was given to 689 patients [age 69 (8) years; CHA2DS2-VASc 3.2 (1); 177 with HF; 41 with prior myocardial infarction, coronary artery bypass graft, or percutaneous coronary intervention; 26 with left ventricular hypertrophy >15 mm; median therapy duration 1153 [237, 1828] days]. The primary efficacy outcome occurred less often in patients treated with SCB [3/100 (99/3316) patient-years] than in patients who never received SCB [SCBnever 4.9/100 (150/3083) patient-years, P < 0.001]. There were numerically fewer primary safety outcomes in patients receiving SCB [2.9/100 (96/3359) patient-years] than in SCBnever patients [4.2/100 (135/3220) patient-years, adjusted P = 0.015]. Sinus rhythm at 2 years was similar between groups [SCB 537/610 (88); SCBnever 472/579 (82)]., Conclusion: Long-term therapy with flecainide or propafenone appeared to be safe in the EAST-AFNET 4 trial to deliver effective ERC therapy, including in selected patients with stable cardiovascular disease such as coronary artery disease and stable HF. Clinical Trial Registration ISRCTN04708680, NCT01288352, EudraCT2010-021258-20, www.easttrial.org., Competing Interests: Conflict of interest: A.R.: Consultant fees, travel grants or lecture fees from Medtronic, Biosense Webster, Abbott, Boston Scientific, Ablamap, Philips, Cardiofocus, Bayer, Pfizer and Novartis, Edwards and Lifetech. Committee: German Society of Cardiology (Select-chair of EP community). L.E.: Grants/contracts: research support by the German heart foundation. Consulting fees Boston Scientific, lecture fees for various medical companies. Society, committee: German Society of Cardiology; European Society of Cardiology; European Heart Rhythm Society. K.B.: no COIs. J.C.: Participation on a data safety monitoring board: Anthos, Johnson and Johnson, Enso, Bayer, Charité. H.C.: Grants/contracts: ZonMw grant no. 104021005 RACE 9 Device-based rate vs. rhythm control treatment in patients with symptomatic recent-onset atrial fibrillation in the emergency department (RACE 9). Consulting fees: InCarda Therapeutics, Roche, Sanofi, Atricure. Payment or Honoraria: Medtronic. Participation on a data safety monitoring board or advisory board: Chair DSMB Decision trial. Committee/society: DZHK, German Centre for Cardiovascular research. A.G.: Grants/contracts: Maestria Grant EU 965286. Consulting fees: Sanofi-Aventis, Bayer, Astra Zeneca, Daiichi Sankyo, BMS/Pfizer, Viofor, Boston Scientific, Medtronic, Menarini. G.B.: Chair, advisory board to AFNET e.V., no payment. M.L.: No COIs. A.M.: Consulting fees: Medtronic, Johnson and Johnson, Boston Scientific, LifeTech. Lecture honoraria: Medtronic, Johnson and Johnson, Lifetech, Pfizer, Boston Scientific, Bayer, Bristol Meyer Squibb. L.R.: No COIs. U.S.: Grants/contracts: EU: CATCH ME, MAESTRIA, Personalize AF, REPAIR, Dutch Heart foundation, RACE V Embrace. Consulting fees: Roche advisory board, YourRhythmics BV. Payment or honoraria: Johnson and Johnson. Patents: non-invasive classification of AF with ECG. Society/Committee: Board of directors of AFNET. Stock or stock options: YourRhythmics BV. E.V.: Support for present manuscript: AFNET: payments made to my institution. Outside this work: Biotronik: payments made to my institution. K.W.: All support payment for manuscript: AFNET. Grants/contracts: Biotronik, Resmed. Payment/honoraria: Boston scientific, Novartis. A.Z.: Support for present manuscript: AFNET: payments made to my institution. Outside this work: Biotronik: payments made to my institution. Grants/contracts: Biotronik, Resmed. Payment/honoraria: Boston scientific. H.H.: Unconditional Research Grants through the University of Hassels and Antwerp: Abbott, Medtronic, Biotronik, Boston scientific, Bayer, Boehringer Ingelheim, Daiichi Sankyo, Pfizer–BMS. Payment or honoraria: Bayer, Biotronik, Bristol Myers Squibb, Daiichi Sankyo, Milestone Pharmaceuticals, Centrix India, CTI Germany, European Society of Cardiology, Medscape, Springer healthcare. Participation on a data safety monitoring board or advisory board: Member, DSBM Prestige-AF. S.W.: Grants: Boston Scientific, Consulting fees: Boston Scientific, Abbott. Speakers Bureau: BSCI; Abbott, BMS, Medtronic. L.F.: Institutional government or charity research support: European Union Horizon 2020 MAESTRIA [grant agreement number 965286 (MAESTRIA)] European Union Horizon 2020 CATCH ME, [grant agreement number 633196 (CATCH ME), European Union Horizon 2020 AFFECT-EU, grant agreement number 847770 (AFFECT-EU)] Institutional governmental support, National Institute for Health and Care Research NIHR, Medical Research Council (UK), German Centre for Cardiovascular Research DZHK. Support for attending meetings: ESC, EHRA, and ESC working groups, ARVC patient organization (charity). Patents planned issued or pending: L.F. is listed as inventor of two patents (Atrial Fibrillation Therapy WO 2015140571, Markers for Atrial Fibrillation WO 2016012783). Society/committee: BHF project grant committee (charity). BHF chair committee visits (charity), AFNET steering committee (charity), ARVC patient organization (charity). Equipment and analytics to AFNET for AFNET 9: Preventicus, Trial costs to AFNET for AFNET 9: Daiichi Sankyo. R.S. has received funding from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme under the grant agreement No 648131, from the European Union’s Horizon 2020 research and innovation programme under the grant agreement no. 847770 (AFFECT-EU) and German Center for Cardiovascular Research (DZHK e.V.) (81Z1710103 and 81Z0710114); German Ministry of Research and Education (BMBF 01ZX1408A) and ERACoSysMed3 (031L0239). Wolfgang Seefried project funding German Heart Foundation. Lecture fees and advisory board fees from BMS/Pfizer and Bayer. Society/committee: ESC stroke council nucleus member. C.M.: Grants or contracts: Research funding from German Center for Cardiovascular Research (Promotion of women scientists programme; FKZ 81X3710112); Deutsche Stiftung für Herzforschung; Dr. Rolf M. Schwiete Stiftung; NDD; Loewenstein Medical. Payment or honoraria: AstraZeneca, Novartis, Boehringer Ingelheim/Lilly, Bayer, Pfizer, Sanofi, Aventis, Apontis, Abbott. Support for attending meetings: AstraZeneca, Novartis, Boehringer Ingelheim/Lilly, Novo Nordisk. Participation on a data safety monitoring board or advisory board: Boehringer Ingelheim/Lilly; Novo Nordisk. P.K.: P.K. was partially supported by European Union AFFECT-AF (grant agreement 847770), and MAESTRIA (grant agreement 965286), British Heart Foundation (PG/17/30/32961; PG/20/22/35093; AA/18/2/34218), German Center for Cardiovascular Research supported by the German Ministry of Education and Research (DZHK, grant numbers DZHK FKZ 81X2800182, 81Z0710116, and 81Z0710110), German Research Foundation (Ki 509167694), and Leducq Foundation. P.K. receives research support for basic, translational, and clinical research projects from European Union, British Heart Foundation, Leducq Foundation, Medical Research Council (UK), and German Centre for Cardiovascular Research, from several drug and device companies active in atrial fibrillation. P.K. is listed as inventor on two issued patents held by University of Hamburg (Atrial Fibrillation Therapy WO 2015140571, Markers for Atrial Fibrillation WO 2016012783). P.K. receives research support for basic, translational, and clinical research projects from European Union, British Heart Foundation, Leducq Foundation, Medical Research Council (UK), and German Center for Cardiovascular Research, from several drug and device companies active in atrial fibrillation, and has received honoraria from several such companies in the past, but not in the last 3 years. P.K. is board member of the ESC and speaker of the board AFNET., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Aims: Recent trial data demonstrate beneficial effects of active rhythm management in patients with atrial fibrillation (AF) and support the concept that a low arrhythmia burden is associated with a low risk of AF-related complications. The aim of this document is to summarize the key outcomes of the 9th AFNET/EHRA Consensus Conference of the Atrial Fibrillation NETwork (AFNET) and the European Heart Rhythm Association (EHRA)., Methods and Results: Eighty-three international experts met in Münster for 2 days in September 2023. Key findings are as follows: (i) Active rhythm management should be part of the default initial treatment for all suitable patients with AF. (ii) Patients with device-detected AF have a low burden of AF and a low risk of stroke. Anticoagulation prevents some strokes and also increases major but non-lethal bleeding. (iii) More research is needed to improve stroke risk prediction in patients with AF, especially in those with a low AF burden. Biomolecules, genetics, and imaging can support this. (iv) The presence of AF should trigger systematic workup and comprehensive treatment of concomitant cardiovascular conditions. (v) Machine learning algorithms have been used to improve detection or likely development of AF. Cooperation between clinicians and data scientists is needed to leverage the potential of data science applications for patients with AF., Conclusions: Patients with AF and a low arrhythmia burden have a lower risk of stroke and other cardiovascular events than those with a high arrhythmia burden. Combining active rhythm control, anticoagulation, rate control, and therapy of concomitant cardiovascular conditions can improve the lives of patients with AF., Competing Interests: Conflict of interest The 9th AFNET/EHRA consensus conference was partially supported by the European Union MAESTRIA project (grant agreement 965286) to AFNET. The following participants and authors are employees of companies active in cardiovascular health as indicated in their affiliations: M.D.M., E.D., C.E., G.H., L.H.H., T.H., R.H.v.L., M.W., and H.W. P.K. was partially supported by the European Union AFFECT-AF (grant agreement 847770) and MAESTRIA (grant agreement 965286), German Center for Cardiovascular Research supported by the German Ministry of Education and Research (DZHK, grant numbers DZHK FKZ 81X2800182, 81Z0710116, and 81Z0710110), German Research Foundation (Ki 509167694), and Leducq Foundation. He receives research support for basic, translational, and clinical research projects from several drug and device companies active in AF and has received honoraria from several such companies in the past, but not in the last 3 years. He is listed as an inventor on two issued patents held by the University of Hamburg (Atrial Fibrillation Therapy WO 2015140571, Markers for Atrial Fibrillation WO 2016012783). J.G.A. was partially supported by the Canadian Arrhythmia Network and the Michael Smith Foundation for Health Research, Baylis Medical. He receives consulting fees/honoraria from Bayer, BMS/Pfizer Alliance, Servier, and Medtronic Inc. E.A. receives consulting fees/honoraria from Biosense Webster and Bayer. G.B. receives consulting fees/honoraria from Bayer, BMS, Boston Scientific, Daiichi Sankyo, Sanofi, and Janssen. A.J.C. receives consulting fees/honoraria from Bayer, Pfizer/BMS, Daiichi Sankyo, Menarini, Sanofi, Boston Scientific, Biosense Webster, Abbott, Acesion Pharma, Huya Bio, and Milestone. V.C. receives consulting fees/honoraria from Bayer, Boehringer Ingelheim, and Ever Pharma (paid to the institution of employment). W.D. receives consulting fees/honoraria from Reata and research grants from MicroPort, Boston Scientific, and Abbott. S.Z.D. receives consulting fees from BMS/Pfizer, Cortrium, and Acesion Pharma and speaker fees from MS/Pfizer and Bayer. He is listed as a medical advisor for Vital Beats. Dobromir D. receives consulting fees/honoraria from Elsevier, Springer Healthcare Ltd, and Daiichi Sankyo and research grants as follows: four NIH grants (partially) from Baylor College of Medicine, Houston; one NIH grant from UC Davis, one NIH grant from the University of Minnesota, and one EU-Project H2020. David D. receives consulting fees/honoraria from Abbott, Astra Zeneca, Biotronik, Boehringer Ingelheim, Boston Scientific, BMS/Pfizer, CVRx, Medtronic, MicroPort, and Zoll and research grants from Roche, CVRx, and Zoll. L.E. has received lecture fees from various companies in AF in the past but none related to the present work. L.F. receives consulting fees/honoraria from Roche (paid to the institution of employment). She is currently employed at the UKE and previously at the University of Birmingham. She was partially supported by the European Union AFFECT-EU (grant agreement 847770), MAESTRIA (grant agreement 965286), CATCH ME (grant agreement 633196), and the British Heart Foundation (AA/18/2/3218). D.F.-R. receives research grants from Abbott. He is listed as an inventor on two issued patents: EP3636147A1 (method for the identification of cardiac fibrillation drivers and/or the footprint of rotational activations) and PCT/EP2022/071364 (system and method of assessment of electromechanical remodelling). A.G. receives consulting fees/honoraria from Daiichi Sankyo, Bayer, BMS/Pfizer, Medtronic, Abbott, and Boston Scientific and was partially supported by the European Union MAESTRIA (grant agreement 965286). K.G.H. receives consulting fees/honoraria from Abbott, Alexion, Amarin, Astra Zeneca, Bayer Healthcare, Biotronik, Boehringer Ingelheim, Boston Scientific, BMS/Pfizer, Daiichi Sankyo, Edwards Lifesciences, Medtronic, Novaris, Portola, Premier Research, Sanofi, SUN Pharma, and W. L. Gore and Associates. J.S.H. receives speaking fees from BMS/Pfizer, Bayer, Servier, and Boston Scientific and consulting fees from Bayer and Boston Scientific. He receives research grants from BMS/Pfizer, Servier, Novartis, Boston Scientific, and Medtronic. H.H. receives lecture and consulting fees from Bayer, Biotronik, BMS/Pfizer, Daiichi Sankyo, Milestone Pharmaceuticals, Centrix India, C.T.I. Germany, ESC, Medscape, and Springer Healthcare Ltd. He receives research grants (paid to the institution of employment, University of Antwerp and/or University of Hasselt) from Abbott, Bayer, Biosense Webster, Boston Scientific, Daiichi Sankyo, Fibricheck/Qompium, Medtronic, and BMS/Pfizer. Z.H. receives consulting fees/honoraria from Boehringer Ingelheim, BMS/Pfizer, and Roche Diagnostics. He was partially supported by The Swedish Society for Medical Research (S17-0133), Hjärt-Lungfonden (The Swedish Heart-Lung Foundation, 20200722), and the institution he is currently employed at (Uppsala University Hospital). L.H.-M. receives research grants from the Spanish Ministry of Science and Innovation (PID2020-116927RB-C21) and Fondo Europeo de Desarrollo Regional (FEDER). D.K. receives consulting fees/honoraria from Bayer, Amomed, and Protherics Medicines Development. He receives research grants from the National Institute for Health Research (NIHR CDF-2015-08-074 RAE-AF; NIHR130280 DaRe2THINK; NIHR13274 D2T-NeuroVascular; and NIHR203326 Biomedical Research Centre), the British Heart Foundation (PG/17/55/33087, AA/182/3218, and FS/CDRF/21/21032), the EU/EFPIA Innovative Medicines Initiative (BigData@Heart 116074), EU Horizon and UKRI (HYPERMARKER 101095480) UK National Health Service—Data for R&D-Subnational Secure Data Environment programme, UK Department for Business, Energy Industrial Strategy Regulators Pioneer Fund, the Cook & Wolstenholme Charitable Trust, and the European Society of Cardiology supported by educational grants from Boehringer Ingelheim, BMS/Pfizer, Alliance, Bayer, Daiichi Sankyo, Boston Scientific, the NIHR/University of Oxford Biomedical Research Centre, and the British Hear Foundation, the University of Birmingham Accelerator Award (STEEER-AF). J.L.M. receives consulting fees/honoraria from Biotronik, Medtronic, MicroPort, and Milestone Pharmaceuticals. A.M. receives consulting fees/honoraria from Medtronic, Biosense Webster, and Boston Scientific and lecture fees from Medtronic, Boston Scientific, Biosense Webster, BMS, and Bayer. L.M. receives consulting fees/honoraria from Abbott, Medtronic, Boston Scientific, and Johnson & Johnson. G.A.N. receives lecture fees from AliveCor, consultant fees from Biosense Webster, and research grants from Abbott and Biosense Webster. H.P. receives consulting fees/honoraria from Abbott, Boston Scientific, Biosense Webster, Medtronic, Daiichi Sankyo, Bayer, and Pfizer. P.S. receives consulting fees/honoraria from Medtronic, Boston Scientific, Abbott, CathRx, and PaceMate (paid to the institution of employment). He is currently employed at the University of Adelaide, which receives research grants from Medtronic, Boston Scientific, and Becton-Dickenson. R.B.S. receives consulting fees/honoraria from BMS/Pfizer. She was partially supported by the European Union Horizon 2020 research and innovation programme (grant agreement 648131 and 847770), German Center for Cardiovascular Research supported by the German Ministry of Education and Research (DZHK, grant numbers 81Z1710103 and 81Z0710114), German Ministry of Research and Education (BMBF 01ZX1408A), ERACoSysMed3 (031L0239), Wolfgang Seefried project funding German Heart Foundation. U.S. receives consulting fees/honoraria from University Svizzerra Italiana, Stanford, and Johnson & Johnson and research grants from the European Union, Dutch Heart Foundation, Roche, and EP Solution. He is a shareholder of YourRhythmics B.V. T.T. receives consulting fees/honoraria from Boston Scientific and Medtronic. I.C.v.G. receives consulting fees/honoraria from Bayer (paid to the institution of employment). She is currently employed at the University of Groningen. K.V. receives consulting fees/honoraria from Abbott, Philips, Medtronic, Biosense Webster, and Boston Scientific and research grants from Medtronic and Biosense Webster. R.W. receives consulting fees/honoraria from Boehringer Ingelheim, BMS/Pfizer, Daiichi Sankyo, Boston Scientific, Biotronik, Abiomed, and Zoll and a research grant from Boston Scientific, BMS/Pfizer, and Abiomed. S.W. receives consulting fees/honoraria from Boehringer Ingelheim, Boston Scientific, Abbott, and Bayer Vital and a research grant from Boston Scientific. All remaining authors (G.B., J.C.N., T.D.P., N.D., M.F., E.G., S.H., S.K., D.L., K.M.-R., M.O., A.S.P., U.R., M.R., D.S., C.S., G.S., D.S., S.T., R.H.v.L., and S.Z.) have declared no conflicts of interest., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

The introduction of His bundle electrography by Benjamin Scherlag (New York) in 1969, together with programmed stimulation of the heart by Philip Coumel (Paris) in 1967, and Hein Wellens (Amsterdam) in 1972, were decisive turning points on the way to invasive electrophysiology and the development of an independent, now distinctly interventional subspecialty of cardiology. The main topic of the 1970s was bradycardic arrhythmias, promoted by pacemaker therapy, which had been introduced just over 10 years earlier. The recording of the potentials of the bundle of His and other recording locations in the atria and ventricles allowed a differentiated assessment of the excitation process and the refractory periods. High-rate atrial stimulation to determine sinus node recovery time and premature stimulation to determine sinoatrial conduction time were developed to analyze sinoatrial node function. This article describes the introduction of His bundle electrography in a gradually increasing number of centers in Germany and their scientific contribution., (© 2024. The Author(s).)

Social media (SoMe) has witnessed remarkable growth and emerged as a dominant method of communication worldwide. Platforms such as Facebook, X (formerly Twitter), LinkedIn, Instagram, TikTok, and YouTube have become important tools of the digital native generation. In the field of medicine, particularly, cardiology, attitudes towards SoMe have shifted, and professionals increasingly utilize it to share scientific findings, network with experts, and enhance teaching and learning. Notably, SoMe is being leveraged for teaching purposes, including the sharing of challenging and intriguing cases. However, sharing patient data, including photos or images, online carries significant implications and risks, potentially compromising individual privacy both online and offline. Privacy and data protection are fundamental rights within European Union treaties, and the General Data Protection Regulation (GDPR) serves as the cornerstone of data protection legislation. The GDPR outlines crucial requirements, such as obtaining 'consent' and implementing 'anonymization', that must be met before sharing sensitive and patient-identifiable information. Additionally, it is vital to consider the patient's perspective and prioritize ethical and social considerations when addressing challenges associated with sharing patient information on SoMe platforms. Given the absence of a peer-review process and clear guidelines, we present an initial approach, a code of conduct, and recommendations for the ethical use of SoMe. In conclusion, this comprehensive review underscores the importance of a balanced approach that ensures patient privacy and upholds ethical standards while harnessing the immense potential of SoMe to advance cardiology practice and facilitate knowledge dissemination., Competing Interests: Conflict of interest: A.J.C. has received personal fees from Bayer, Bristol-Myers Squibb, Daiichi Sankyo, Pfizer, Abbott, Boston Scientific, Medtronic, Sanofi, and Menarini. R.B. has received an independent research grant to the institute from Abbott and a speaker fee from Abbott, Bayer, and Boehringer Ingelheim outside the scope of the submitted work., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Background: Non-vitamin K oral anticoagulants have become the standard therapy for preventing stroke and ischemic thromboembolism in most patients with atrial fibrillation (AF). The effectiveness and safety of non-vitamin K oral anticoagulants in patients on hemodialysis is not well known., Methods: From June 2017 through May 2022, AXADIA-AFNET 8 (Compare Apixaban and Vitamin K Antagonists in Patients With Atrial Fibrillation and End-Stage Kidney Disease), an investigator-initiated PROBE (prospective randomized open blinded end point) outcome assessment trial, randomized patients with AF on chronic hemodialysis to either apixaban (2.5 mg BID) or the vitamin K antagonist (VKA) phenprocoumon (international normalized ratio, 2.0 to 3.0). The composite primary safety outcome was defined by a first event of major bleeding, clinically relevant nonmajor bleeding, or all-cause death. The primary efficacy outcome was a composite of ischemic stroke, all-cause death, myocardial infarction, and deep vein thrombosis or pulmonary embolism. Our hypothesis was that apixaban is noninferior to VKA., Results: Thirty-nine sites randomized 97 patients (30% women; mean age 75 years; mean CHA 2 DS 2 -VASc [congestive heart failure, hypertension, age ≥75 years, diabetes, stroke or transient ischemic attack, vascular disease, age 65 to 74 years, female sex] score, 4.5; baseline characteristics balanced between groups): 48 to apixaban and 49 to VKA. The median follow-up time was 429 days (range, 37 to 1370) versus 506 days (range, 101 to 1379), respectively. Adherence to apixaban was >80% in 44 of 48 patients; the median time in therapeutic range on VKA was 50.7%. Composite primary safety outcome events occurred in 22 patients (45.8%) on apixaban and in 25 patients (51.0%) on VKA (hazard ratio, 0.93 [95% CI, 0.53-1.65]; P noninferiority =0.157). Composite primary efficacy outcome events occurred in 10 patients (20.8%) on apixaban and in 15 patients (30.6%) on VKA ( P =0.51; log rank). There were no significant differences regarding individual outcomes (all-cause mortality, 18.8% versus 24.5%; major bleeding, 10.4% versus 12.2%; and myocardial infarction, 4.2% versus 6.1%, respectively)., Conclusions: In this randomized trial comparing apixaban and VKA in patients with AF on hemodialysis with long follow-up, no differences were observed in safety or efficacy outcomes. Even on oral anticoagulation, patients with AF on hemodialysis remain at high risk of cardiovascular events. Larger randomized trials are needed to determine the optimal anticoagulation regimen for patients with AF on hemodialysis., Registration: URL: https://www., Clinicaltrials: gov; Unique identifier: NCT02933697.

Aims: A strategy of systematic, early rhythm control (ERC) improves cardiovascular outcomes in patients with atrial fibrillation (AF). It is not known how this outcome-reducing effect is mediated., Methods and Results: Using the Early treatment of Atrial Fibrillation for Stroke prevention Trial (EAST-AFNET 4) data set, potential mediators of the effect of ERC were identified in the total study population at 12-month follow up and further interrogated by use of a four-way decomposition of the treatment effect in an exponential model predicting future primary outcome events. Fourteen potential mediators of ERC were identified at the 12-month visit. Of these, sinus rhythm at 12 months explained 81% of the treatment effect of ERC compared with usual care during the remainder of follow up (4.1 years). In patients not in sinus rhythm at 12 months, ERC did not reduce future cardiovascular outcomes (hazard ratio 0.94, 95% confidence interval 0.65-1.67). Inclusion of AF recurrence in the model only explained 31% of the treatment effect, and inclusion of systolic blood pressure at 12 months only 10%. There was no difference in outcomes in patients who underwent AF ablation compared with those who did not undergo AF ablation., Conclusion: The effectiveness of early rhythm control is mediated by the presence of sinus rhythm at 12 months in the EAST-AFNET 4 trial. Clinicians implementing ERC should aim for rapid and sustained restoration of sinus rhythm in patients with recently diagnosed AF and cardiovascular comorbidities., Competing Interests: Conflict of interest: L.E. discloses consultant fees, speaking honoraria, and travel expenses from Abbott, Bayer Healthcare, Biosense Webster, Biotronik, Boehringer, Boston Scientific, Bristol-Myers Squibb, Daiichi Sankyo, Medtronic, Pfizer, and Sanofi Aventis. Research has been supported by German Research Foundation (DFG) and German Heart Foundation outside the submitted work. S.S. reports grants from AFNET, during the conduct of the study; grants from Biotronik, personal fees from Boston Scientific and grants from ResMed, outside the submitted work. A.S. reports grants from AFNET, during the conduct of the study; grants from BIOTRONIK and grants from ResMed, outside the submitted work. K.B. declares that there is no conflict of interest. G.B. reports no potential conflicts of interest with regard to the present substudy of EAST. H.J.G.M.C. reports support from The Netherlands Cardiovascular Research Initiative: an initiative with support of the Dutch Heart Foundation, CVON 2014-9: reappraisal of atrial fibrillation: interaction between hypercoagulability, electrical remodelling, and vascular destabilization in the progression of AF (RACE V), outside this work. A.G. reports speaker and consulting fees from Bayer Health Care, Berlin Chemie, Boehringer Ingelheim, BMS/Pfizer, Boston Scientific, Daiichi Sankyo, Medtronic, Omeicos, and Menarini; grants from EU Horizon 2020 [grant no. 965286] and grants from AFNET, Sanofia-Aventis, and St Jude Medical during the conduct of the study. K.W. reports grants from AFNET, during the conduct of the study; grants from Biotronik, personal fees from Biotronik, personal fees from Boston Scientific, grants from ResMed and personal fees from Novartis, outside the submitted work. A.Z. reports grants from AFNET, during the conduct of the study; grants from Biotronik, personal fees from Boston Scientific and grants from ResMed, outside the submitted work. A.J.C. reports personal fees from Abbott and Sanofi and institutional grants from Abbott for work unrelated to the EAST trial. A.M. reports consulting fees from Medtronic and Biosense Webster; speaker fees from Medtronic, Biosense Webster, Boston Scientific, and Bayer; travel support from Medtronic and Boston Scientific. P.K. reports grants and nonfinancial support from BMBF (German Ministry of Education and Research), grants from Sanofi, grants from Abbott, grants and nonfinancial support from EHRA, grants from German Heart Foundation, grants from DZHK (German Center for Cardiovascular Research), during the conduct of the study; grants from European Union, grants from British Heart Foundation, grants from Leducq Foundation, grants from Medical Research Council (UK), non-financial support from German Centre for Heart Research, outside the submitted work. In addition, P.K. has a patent Atrial Fibrillation Therapy WO 2015140571 issued to University of Birmingham, and a patent Markers for Atrial Fibrillation WO 2016012783 issued to University of Birmingham., (© The Author(s) 2022. Published by Oxford University Press on behalf of European Society of Cardiology.)

Background: The randomized EAST-AFNET4 (Early Treatment of Atrial Fibrillation for Stroke Prevention Trial-Atrial Fibrillation Network) demonstrated that early rhythm control (ERC) reduces adverse cardiovascular outcomes in patients with recently diagnosed atrial fibrillation and stroke risk factors. The effectiveness and safety of ERC in patients with multiple cardiovascular comorbidities is not known., Methods: These prespecified subanalyses of EAST-AFNET4 compared the effectiveness and safety of ERC with usual care (UC) stratified into patients with higher (CHA 2 DS 2 -VASc score ≥4) and lower comorbidity burden. Sensitivity analyses ignored sex (CHA 2 DS 2 -VA score)., Results: EAST-AFNET4 randomized 1093 patients with CHA 2 DS 2 -VASc score ≥4 (74.8±6.8 years, 61% female) and 1696 with CHA 2 DS 2 -VASc score <4 (67.4±8.0 years, 37% female). ERC reduced the composite primary efficacy outcome of cardiovascular death, stroke, or hospitalization for worsening of heart failure or for acute coronary syndrome in patients with CHA 2 DS 2 -VASc score ≥4 (ERC, 127/549 patients with events; UC, 183/544 patients with events; hazard ratio [HR], 0.64 [0.51-0.81]; P < 0.001) but not in patients with CHA 2 DS 2 -VASc score <4 (ERC, 122/846 patients with events; UC, 133/850 patients with events; HR, 0.93 [0.73-1.19]; P =0.56, P interaction =0.037). The primary safety outcome (death, stroke, or serious adverse events of rhythm control therapy) was not different between study groups in patients with CHA 2 DS 2 -VASc score ≥4 (ERC, 112/549 patients with events; UC, 132/544 patients with events; HR, 0.84 [0.65, 1.08]; P =0.175), but occurred more often in patients with CHA 2 DS 2 -VASc scores <4 randomized to ERC (ERC, 119/846 patients with events; UC, 91/850 patients with events; HR, 1.39 [1.05-1.82]; P =0.019, P interaction =0.008). Life-threatening events or death were not different between groups (CHA 2 DS 2 -VASc score ≥4, ERC, 84/549 patients with event, UC, 96/544 patients with event; CHA 2 DS 2 -VASc scores <4, ERC, 75/846 patients with event, UC, 73/850 patients with event). When female sex was ignored for the creation of higher and lower risk groups (CHA 2 DS 2 -VA score), the P interaction was not significant for the primary efficacy outcome ( P =0.25), but remained significant ( P =0.044) for the primary safety outcome., Conclusions: Patients with recently diagnosed atrial fibrillation and CHA 2 DS 2 -VASc score ≥4 should be considered for ERC to reduce cardiovascular outcomes, whereas those with fewer comorbidities may have less favorable outcomes with ERC., Registration: URL: https://www., Clinicaltrials: gov; Unique identifier: NCT01288352. URL: https://www.clinicaltrialsregister.eu; Unique identifier: 2010-021258-20. URL: https://www.isrctn.com/; Unique identifier: ISRCTN04708680.

Background: Whether atrial fibrillation (AF) pattern or timing of AF therapy modifies the effectiveness of early rhythm control (ERC) is not known., Objectives: This study sought to compare clinical characteristics and outcomes in patients presenting with different AF patterns on ERC vs usual care., Methods: The effects of ERC were compared in first-diagnosed AF (FDAF), paroxysmal AF (paroxAF), and persistent AF (persAF) in this prespecified analysis of the EAST-AFNET 4 (Early treatment of atrial fibrillation for stroke prevention) trial. Associations between AF pattern and primary outcomes (first primary outcome: cardiovascular death, stroke, and hospitalization for heart failure and acute coronary syndrome; second primary outcome: nights spent in hospital per year) were compared over a mean follow-up of 5.1 years. Changes in health-related quality of life were assessed by the EQ-5D., Results: FDAF patients (n = 1,048, enrolled 7 days after diagnosing AF) were slightly older (71 years of age, 48.0% female) than patients with paroxAF (n = 994, 70 years of age, 50.0% female) and persAF (n = 743, 70 years of age, 38.0% female). ERC reduced the primary outcome in all 3 AF patterns. Hospitalizations for acute coronary syndrome were highest in FDAF (incidence rate ratio [IRR]: 1.50; 95% CI: 0.83-2.69; P for interaction = 0.032) compared with paroxAF (IRR: 0.64; 95% CI: 0.32-1.25) and persAF (IRR: 0.50; 95% CI: 0.25-1.00). FDAF patients spent more nights in hospital (IRR: 1.38; 95% CI: 1.12-1.70; P for interaction = 0.004) than paroxAF (IRR: 0.84; 95% CI: 0.67-1.03), and persAF (IRR: 1.02; 95% CI: 0.80-1.30) patients. ERC improved health-related quality of life (EQ-5D score) in patients with paroxAF and persAF but not in patients with FDAF (P = 0.019)., Conclusions: ERC reduces the first primary composite outcome in all AF patterns. Patients with FDAF are at high risk for hospitalization and acute coronary syndrome, particularly on ERC. (Early treatment of atrial fibrillation for stroke prevention trial; ISRCTN04708680; Early Treatment of Atrial Fibrillation for Stroke Prevention Trial [EAST]; NCT01288352; Early treatment of Atrial fibrillation for Stroke prevention Trial [EAST]; EudraCT2010-021258-20)., Competing Interests: Funding Support and Author Disclosures Dr Goette was partially supported by the EU Horizon 2020 MAESTRIA Consortium (grant number 965286). Dr Kirchhof was partially supported by the EU BigData@Heart (grant agreement EU IMI 116074), AFFECT-AF (grant agreement 847770), and MAESTRIA (grant agreement 965286); the British Heart Foundation (PG/17/30/32961; PG/20/22/35093; AA/18/2/34218), the German Centre for Cardiovascular Research supported by the German Ministry of Education and Research, and the Leducq Foundation. The EAST-AFNET 4 trial was supported by AFNET, the European Heart Rhythm Association, the German Centre for Cardiovascular Research, the German Heart Foundation, Sanofi, and Abbott. Dr Goette has received speaker fees from Abbott, AstraZeneca, Bayer Health Care, Berlin Chemie, Biotronik, Boehringer Ingelheim, BMS/Pfizer, Boston Scientific, Daiichi-Sankyo, Medtronic, Omeicos, Sanofi, and Viofor. Dr Camm has served as an advisor for Bayer, Daiichi-Sankyo, Pfizer/BMS, Medtronic, Boston Scientific, Abbott, Menarini, and Sanofi. Dr Kuck has served as a consultant for CardioValve; and has received grant support from Medtronic and Biosense Webster. Dr Wegscheider has served as a lecturer and statistical consultant for Biotronik, Boston Scientific, and Novartis; and has received grant support from Biotronik and Resmed. Dr Kirchhof has received research support for basic, translational, and clinical research projects from the European Union, British Heart Foundation, Leducq Foundation, Medical Research Council (United Kingdom), and German Centre for Cardiovascular Research and from several drug and device companies active in atrial fibrillation; has received honoraria from several such companies in the past, but not in the last 3 years; and has been listed as inventor on 2 patents held by University of Birmingham (Atrial Fibrillation Therapy WO 2015140571, Markers for Atrial Fibrillation WO 2016012783). All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Aims: To evaluate the effectiveness and safety of dronedarone compared with other commonly used antiarrhythmic drugs (AADs) for preventing atrial fibrillation (AF) recurrences., Methods and Results: An international observational cohort study in Germany, Spain, Italy, and the USA enrolling patients with AF receiving AAD therapy. Patients with New York Heart Association (NYHA) Class IV heart failure were excluded. Participants were followed for up to 18 months, regardless of discontinuation or subsequent AAD switches. Atrial fibrillation recurrence was captured by hospitalization, emergency room visit, or electrocardiogram-based documentation of AF. Confounding bias was controlled for in the analysis of AF recurrence using multivariate models of 19 variables for adjustment. A total of 1009 participants [mean age 67.2 (10.8) years, male to female ratio 1.3] were recruited from 170 centres, 693 (69%) of which were from across Europe and the remaining 316 (31%) from the USA. At the time of enrolment, participants were taking dronedarone (51%) or other AADs (49%) [flecainide or propafenone (42%), sotalol (11%), and amiodarone (47%)]. No significant differences in the risk of first confirmed AF recurrence with dronedarone vs. other AADs [crude hazard ratio (HR) 1.10 (95% confidence interval 0.85-1.42); adjusted HR 1.16 (0.87-1.55)] were found, irrespective of whether univariate or multivariate models were used. Reported safety events were in accordance with the known safety profile of dronedarone., Conclusion: In this population of patients from either Europe or the USA receiving dronedarone or another AAD, the effectiveness of dronedarone was comparable to that observed for other AADs in preventing first AF recurrence., (© The Author(s) 2021. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Background: Amiodarone has a profound adverse toxicity profile. Large population-based analyses quantifying the risk of thyroid dysfunction (TD) in adults with and without congenital heart disease (ACHD) are lacking. Methods: All adults registered with a major German health insurer (≈9.2 million members) with amiodarone prescriptions were analyzed. Occurrence of amiodarone-associated TD was assessed. Results: Overall, 48,891 non-ACHD (37% female; median 73 years) and 886 ACHD (34% female; median 66 years) received amiodarone. Over 184,787 patient-years, 10,875 cases of TD occurred. The 10-year risk for TD was 38% in non-ACHD (35% ACHD). Within ACHD, compared to amiodarone-naïve patients, the hazard ratio (HR) for TD was 3.9 at 4 years after any amiodarone exposure. TD was associated with female gender (HR 1.42, p < 0.001) and younger age (HR 0.97 per 10 years, p = 0.009). Patients with congenital heart disease were not at increased risk (HR 0.98, p = 0.80). Diagnosis of complex congenital heart disease, however, was a predictor for TD (HR 1.56, p = 0.02). Amiodarone was continued in 47% of non-ACHD (38% ACHD), and 2.3% of non-ACHD (3.5% ACHD) underwent thyroid surgery/radiotherapy. Conclusions: Amiodarone-associated TD is common and comparable in non-ACHD and ACHD. While female gender and younger age are predictors for TD, congenital heart disease is not necessarily associated with an elevated risk.

Aims: Treatment patterns were compared between randomized groups in EAST-AFNET 4 to assess whether differences in anticoagulation, therapy of concomitant diseases, or intensity of care can explain the clinical benefit achieved with early rhythm control in EAST-AFNET 4., Methods and Results: Cardiovascular treatment patterns and number of visits were compared between randomized groups in EAST-AFNET 4. Oral anticoagulation was used in >90% of patients during follow-up without differences between randomized groups. There were no differences in treatment of concomitant conditions between groups. The type of rhythm control varied by country and centre. Over time, antiarrhythmic drugs were given to 1171/1395 (84%) patients in early therapy, and to 202/1394 (14%) in usual care. Atrial fibrillation (AF) ablation was performed in 340/1395 (24%) patients randomized to early therapy, and in 168/1394 (12%) patients randomized to usual care. 97% of rhythm control therapies were within class I and class III recommendations of AF guidelines. Patients randomized to early therapy transmitted 297 166 telemetric electrocardiograms (ECGs) to a core lab. In total, 97 978 abnormal ECGs were sent to study sites. The resulting difference between study visits was low (0.06 visits/patient/year), with slightly more visits in early therapy (usual care 0.39 visits/patient/year; early rhythm control 0.45 visits/patient/year, P < 0.001), mainly due to visits for symptomatic AF recurrences or recurrent AF on telemetric ECGs., Conclusion: The clinical benefit of early, systematic rhythm control therapy was achieved using variable treatment patterns of antiarrhythmic drugs and AF ablation, applied within guideline recommendations., (© The Author(s) 2021. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Aims: Clinical practice guidelines restrict rhythm control therapy to patients with symptomatic atrial fibrillation (AF). The EAST-AFNET 4 trial demonstrated that early, systematic rhythm control improves clinical outcomes compared to symptom-directed rhythm control., Methods and Results: This prespecified EAST-AFNET 4 analysis compared the effect of early rhythm control therapy in asymptomatic patients (EHRA score I) to symptomatic patients. Primary outcome was a composite of death from cardiovascular causes, stroke, or hospitalization with worsening of heart failure or acute coronary syndrome, analyzed in a time-to-event analysis. At baseline, 801/2633 (30.4%) patients were asymptomatic [mean age 71.3 years, 37.5% women, mean CHA2DS2-VASc score 3.4, 169/801 (21.1%) heart failure]. Asymptomatic patients randomized to early rhythm control (395/801) received similar rhythm control therapies compared to symptomatic patients [e.g. AF ablation at 24 months: 75/395 (19.0%) in asymptomatic; 176/910 (19.3%) symptomatic patients, P = 0.672]. Anticoagulation and treatment of concomitant cardiovascular conditions was not different between symptomatic and asymptomatic patients. The primary outcome occurred in 79/395 asymptomatic patients randomized to early rhythm control and in 97/406 patients randomized to usual care (hazard ratio 0.76, 95% confidence interval [0.6; 1.03]), almost identical to symptomatic patients. At 24 months follow-up, change in symptom status was not different between randomized groups (P = 0.19)., Conclusion: The clinical benefit of early, systematic rhythm control was not different between asymptomatic and symptomatic patients in EAST-AFNET 4. These results call for a shared decision discussing the benefits of rhythm control therapy in all patients with recently diagnosed AF and concomitant cardiovascular conditions (EAST-AFNET 4; ISRCTN04708680; NCT01288352; EudraCT2010-021258-20)., (© The Author(s) 2021. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Aims: Atrial fibrillation (AF) is associated with a high risk of cardiovascular and non-cardiovascular death, even on anticoagulation. It is controversial, which conditions-including concomitant diseases and AF itself-contribute to this mortality. To further clarify these questions, major determinants of long-term mortality and their contribution to death were quantified in an unselected cohort of AF patients., Methods and Results: We established a large nationwide registry comprising 8833 AF-patients with a median follow-up of 6.5 years (45 345 patient-years) and central adjudication of adverse events. Baseline characteristics of the patients were evaluated as predictors of mortality using Cox regression and C-indices for determination of predictive power. Annualized mortality was highest in the first year (6.2%) and remained high thereafter (5.2% in men and 5.5% in women). Thirty-eight percent of all deaths were cardiovascular, mainly due to heart failure or sudden death. Sex-specific age was the strongest predictor of mortality, followed by concomitant cardiovascular and non-cardiovascular conditions. These factors accounted for 25% of the total mortality beyond age and sex and for 84% of the mortality differences between AF types. Thus, the electrical phenotype of the disease at baseline contributed only marginally to prediction of mortality., Conclusion: Mortality is high in AF patients and arises primarily from heart failure, peripheral artery disease, chronic obstructive lung disease, chronic kidney disease, and diabetes mellitus, which, therefore, should be targeted to lower mortality. Parameters related to the electrical manifestation of AF did not have an independent impact on long-term mortality in our representative cohort., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: journals.permissions@oup.com.)

Background In event-driven clinical trials, study termination is based on accrual of a target number of primary efficacy events. For noninferiority trials in which superiority is conditionally examined, the ideal cohort in which to track event accrual is unclear. We used data from the ROCKET AF (Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation) trial to determine the effect of primary efficacy-event tracking in the per-protocol cohort during the on-treatment period versus the intention-to-treat (ITT) cohort during the ITT period. Methods and Results ROCKET AF was terminated after accruing 429 primary efficacy events (stroke or systemic embolism) in the per-protocol cohort during the on-treatment period for noninferiority. We identified the date on which 429 events occurred in the ITT cohort during the ITT period. We performed noninferiority and superiority analyses based on hypothetical study termination on this date. ROCKET AF would have terminated 226 days earlier if events were tracked during the ITT period. Similar to the main trial findings, rivaroxaban would have met noninferiority versus warfarin for the primary efficacy end point (hazard ratio [HR], 0.77; 95% CI, 0.62-0.96; P <0.001). In contrast to the main trial findings, rivaroxaban would have met superiority for the primary efficacy end point (HR, 0.82; 95% CI, 0.68-0.99; P =0.038). In both termination scenarios, rivaroxaban was associated with a lower risk of intracranial hemorrhage and similar risk of other safety end points. Conclusions Clinical trial termination based on event accrual in the ITT cohort versus the per-protocol cohort may have important implications on trial results depending on rates of study drug discontinuation and event rates off treatment.

Background: Cardiovascular morbidity and mortality are closely linked to chronic kidney disease (CKD). Sex-specific long-term outcome data of patients with coronary artery disease (CAD) and CKD are scarce., Methods: In the prospective observational multicenter Coronary Artery Disease and REnal Failure (CAD-REF) Registry, 773 (23.1%) women and 2,579 (76.9%) men with angiographically documented CAD and different stages of CKD were consecutively enrolled and followed for up to 8 years. Long-term outcome was evaluated using survival analysis and multivariable Cox-regression models., Results: At enrollment, women were significantly older than men, and suffered from more comorbidities like CKD, hypertension, diabetes mellitus, and multivessel coronary disease. Regarding long-term mortality, no sex-specific differences were observed (Kaplan-Meier survival estimates: 69% in women vs. 69% in men, p log-rank  = 0.7). Survival rates decreased from 89% for patients without CKD at enrollment to 72% for patients with CKD stages 1-2 at enrollment and 49% for patients with CKD stages 3-5 at enrollment (p log-rank  < 0.001). Cox-regression analysis revealed that sex or multivessel coronary disease were no independent predictors of long-term mortality, while age, CKD stages 3-5, albumin/creatinine ratio, diabetes, valvular heart disease, peripheral artery disease, and left-ventricular ejection fraction were predictors of long-term mortality., Conclusions: Sex differences in CAD patients mainly exist in the cardiovascular risk profile and the extent of CAD. Long-term mortality was not depended on sex or multivessel disease. More attention should be given to treatment of comorbidities such as CKD and peripheral artery disease being independent predictors of death. Clinical Trail Registration ClinicalTrials.gov Identifier: NCT00679419., (© 2021. The Author(s).)

Background: Even on optimal therapy, many patients with heart failure and atrial fibrillation experience cardiovascular complications. Additional treatments are needed to reduce these events, especially in patients with heart failure and preserved left ventricular ejection fraction., Methods: This prespecified subanalysis of the randomized EAST-AFNET4 trial (Early Treatment of Atrial Fibrillation for Stroke Prevention Trial) assessed the effect of systematic, early rhythm control therapy (ERC; using antiarrhythmic drugs or catheter ablation) compared with usual care (allowing rhythm control therapy to improve symptoms) on the 2 primary outcomes of the trial and on selected secondary outcomes in patients with heart failure, defined as heart failure symptoms New York Heart Association II to III or left ventricular ejection fraction [LVEF] <50%., Results: This analysis included 798 patients (300 [37.6%] female, median age 71.0 [64.0, 76.0] years, 785 with known LVEF). The majority of patients (n=442) had heart failure and preserved LVEF (LVEF≥50%; mean LVEF 61±6.3%), the others had heart failure with midrange ejection fraction (n=211; LVEF 40%-49%; mean LVEF 44 ± 2.9%) or heart failure with reduced ejection fraction (n=132; LVEF<40%; mean LVEF 31±5.5%). Over the 5.1-year median follow-up, the composite primary outcome of cardiovascular death, stroke, or hospitalization for worsening of heart failure or for acute coronary syndrome occurred less often in patients randomly assigned to ERC (94/396; 5.7 per 100 patient-years) compared with patients randomly assigned to usual care (130/402; 7.9 per 100 patient-years; hazard ratio, 0.74 [0.56-0.97]; P =0.03), not altered by heart failure status (interaction P value=0.63). The primary safety outcome (death, stroke, or serious adverse events related to rhythm control therapy) occurred in 71 of 396 (17.9%) patients with heart failure randomly assigned to ERC and in 87 of 402 (21.6%) patients with heart failure randomly assigned to usual care (hazard ratio, 0.85 [0.62-1.17]; P =0.33). LVEF improved in both groups (LVEF change at 2 years: ERC 5.3±11.6%, usual care 4.9±11.6%, P =0.43). ERC also improved the composite outcome of death or hospitalization for worsening of heart failure., Conclusions: Rhythm control therapy conveys clinical benefit when initiated within 1 year of diagnosing atrial fibrillation in patients with signs or symptoms of heart failure. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01288352. URL: http://www.controlled-trials.com; Unique identifier: ISRCTN04708680. URL: https://www.clinicaltrialsregister.eu; Unique identifier: 2010-021258-20.

Background: ROCKET AF demonstrated the efficacy and safety of rivaroxaban compared with warfarin for the prevention of stroke and systemic embolism (SE) in patients with atrial fibrillation (AF). We examined baseline characteristics and outcomes in patients enrolled in Latin America compared with the rest of the world (ROW)., Methods: ROCKET AF enrolled 14,264 patients from 45 countries. Of these, 1,878 (13.2%) were from 7 Latin American countries. The clinical characteristics and outcomes (adjusted by baseline characteristics) of these patients were compared with 12,293 patients from the ROW. Treatment outcomes of rivaroxaban compared with warfarin were also stratified by region., Results: The annual rate of stroke/SE was similar in those from Latin American and ROW (P= .63), but all-cause and vascular death were significantly higher than in ROW (HR 1.40, 95% CI 1.20-1.64; HR 1.38, 95% CI 1.14-1.68; P< .001). Rates of major or nonmajor clinically relevant bleeding tended to be lower in Latin America (HR 0.89, 95% CI 0.80-1.0; P= .05). Rates of stroke and/or SE were similar with rivaroxaban and warfarin in patients from Latin America and ROW (HR 0.83, 95% CI 0.54-1.29 vs HR 0.89, 95% CI 0.75-1.07; interaction P= .77)., Conclusions: Patients with AF in Latin America had similar rates of stroke and/or SE, higher rates of vascular death, and lower rates of bleeding compared with patients in the ROW. The effect of rivaroxaban compared with warfarin in Latin America was similar to the ROW. Further studies analyzing patient- and country-specific determinants of these regional differences in Latin America are warranted., (Copyright © 2021. Published by Elsevier Inc.)

Background: Insulin use may be a better predictor of stroke risk and morbidity and mortality than diabetes in patients with atrial fibrillation (AF)., Objectives: Determine if the increased risk of stroke observed in patients with AF and diabetes is restricted to those treated with insulin., Methods: We analyzed the association between diabetes and treatment and the occurrence of stroke/systemic embolism, myocardial infarction (MI), all-cause death, vascular death, composite outcomes, and bleeding risk in the ROCKET AF trial., Results: In a cohort of 14,264 patients, there were 40.3% (n = 5746) with diabetes, 5.9% (n = 842) on insulin, 18.9% (n = 2697) on oral medications, and 11.9% (n = 1703) diet-controlled. Compared to those without diabetes, patients with non-insulin-treated diabetes had increased risks of stroke (hazard ratio [HR] 1.33, 95% confidence interval [CI] 1.06-1.68), MI (HR 1.64, 95% CI 1.17-2.30), all-cause death (HR 1.26, 95% CI 1.08-1.46), vascular death (HR 1.33, 95% CI 1.11-1.60), and composite outcomes (HR 1.37, 95% CI 1.18-1.157). Patients with insulin-treated diabetes had a significantly higher risk of MI (HR 2.31, 95% CI 1.33-4.01) and composite outcomes (HR 1.57, 95% CI 1.19-2.08) compared to those without diabetes. There were no significant differences between insulin-treated and non-insulin-treated diabetes for any outcome., Conclusion: Among patients with AF and diabetes, there were no significant differences in outcomes in insulin-treated diabetes compared to non-insulin-treated diabetes., (© 2021 Published by Elsevier Inc. on behalf of Heart Rhythm Society.)

The RACE trial was one of the first landmark trials to establish whether restoring and maintaining sinus rhythm could reduce morbidity and mortality in patients with atrial fibrillation (AF). Its neutral outcome shaped clinical decision-making for almost 20 years. However, there were two important treatment-related factors associated with mortality of rhythm control therapy at that time: One was safety of antiarrhythmic drug therapy, and the other one withdrawal of anticoagulation after restoration of sinus rhythm. Both concerns have been overcome, and, moreover, important knowledge considering the importance of time for the treatment of AF has been gained. These insights led to the concept of the EAST-AFNET 4 trial, and after more than two decades in the pursuit of ongoing therapeutic improvement, early rhythm control therapy has demonstrated to reduce a composite of cardiovascular death, stroke, and hospitalization for worsening of HF or acute coronary syndrome, by 21% (first primary outcome, absolute reduction 1.1 per 100 patient-years). For this entire period, Harry Crijns characterized the treatment of AF patients, and contributed decisively to realizing the benefit of rhythm control therapy. It is almost easier to list the clinical trials without Harry's involvement than to list those which he co-designed and led., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: journals.permissions@oup.com.)

Aims: The risk of developing atrial fibrillation (AF) and its complications continues to increase, despite good progress in preventing AF-related strokes., Methods and Results: This article summarizes the outcomes of the 7th Consensus Conference of the Atrial Fibrillation NETwork (AFNET) and the European Heart Rhythm Association (EHRA) held in Lisbon in March 2019. Sixty-five international AF specialists met to present new data and find consensus on pressing issues in AF prevention, management and future research to improve care for patients with AF and prevent AF-related complications. This article is the main outcome of an interactive, iterative discussion between breakout specialist groups and the meeting plenary. AF patients have dynamic risk profiles requiring repeated assessment and risk-based therapy stratification to optimize quality of care. Interrogation of deeply phenotyped datasets with outcomes will lead to a better understanding of the cardiac and systemic effects of AF, interacting with comorbidities and predisposing factors, enabling stratified therapy. New proposals include an algorithm for the acute management of patients with AF and heart failure, a call for a refined, data-driven assessment of stroke risk, suggestions for anticoagulation use in special populations, and a call for rhythm control therapy selection based on risk of AF recurrence., Conclusion: The remaining morbidity and mortality in patients with AF needs better characterization. Likely drivers of the remaining AF-related problems are AF burden, potentially treatable by rhythm control therapy, and concomitant conditions, potentially treatable by treating these conditions. Identifying the drivers of AF-related complications holds promise for stratified therapy., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2020. For permissions, please email: journals.permissions@oup.com.)

Background: Despite improvements in the management of atrial fibrillation, patients with this condition remain at increased risk for cardiovascular complications. It is unclear whether early rhythm-control therapy can reduce this risk., Methods: In this international, investigator-initiated, parallel-group, open, blinded-outcome-assessment trial, we randomly assigned patients who had early atrial fibrillation (diagnosed ≤1 year before enrollment) and cardiovascular conditions to receive either early rhythm control or usual care. Early rhythm control included treatment with antiarrhythmic drugs or atrial fibrillation ablation after randomization. Usual care limited rhythm control to the management of atrial fibrillation-related symptoms. The first primary outcome was a composite of death from cardiovascular causes, stroke, or hospitalization with worsening of heart failure or acute coronary syndrome; the second primary outcome was the number of nights spent in the hospital per year. The primary safety outcome was a composite of death, stroke, or serious adverse events related to rhythm-control therapy. Secondary outcomes, including symptoms and left ventricular function, were also evaluated., Results: In 135 centers, 2789 patients with early atrial fibrillation (median time since diagnosis, 36 days) underwent randomization. The trial was stopped for efficacy at the third interim analysis after a median of 5.1 years of follow-up per patient. A first-primary-outcome event occurred in 249 of the patients assigned to early rhythm control (3.9 per 100 person-years) and in 316 patients assigned to usual care (5.0 per 100 person-years) (hazard ratio, 0.79; 96% confidence interval, 0.66 to 0.94; P = 0.005). The mean (±SD) number of nights spent in the hospital did not differ significantly between the groups (5.8±21.9 and 5.1±15.5 days per year, respectively; P = 0.23). The percentage of patients with a primary safety outcome event did not differ significantly between the groups; serious adverse events related to rhythm-control therapy occurred in 4.9% of the patients assigned to early rhythm control and 1.4% of the patients assigned to usual care. Symptoms and left ventricular function at 2 years did not differ significantly between the groups., Conclusions: Early rhythm-control therapy was associated with a lower risk of adverse cardiovascular outcomes than usual care among patients with early atrial fibrillation and cardiovascular conditions. (Funded by the German Ministry of Education and Research and others; EAST-AFNET 4 ISRCTN number, ISRCTN04708680; ClinicalTrials.gov number, NCT01288352; EudraCT number, 2010-021258-20.)., (Copyright © 2020 Massachusetts Medical Society.)

Advanced interatrial block (A-IAB) has been associated to atrial fibrillation (AF) and ischemic stroke, raising the question as to whether such patients, even when still in sinus rhythm without documented AF, could benefit from oral anticoagulation. AF and A-IAB are both markers of stroke. The anatomical substrate in both is fibrotic atrial cardiomyopathy, resulting in atrial electromechanical dyssynchrony, dysfunction, and left atrial remodelling, that favour blood stasis and hypercoagulation. Under these conditions thrombogenic cascade may be triggered, resulting in systemic embolization. Before proposing oral anticoagulation in the management of selected patients with A-IAB, as is currently recommended in patients with AF and high CHA 2 DS 2 -Vasc score, a randomized clinical trial will have to demonstrate efficacy and safety of anticoagulation in this setting. In the meantime, an individualized approach may be considered based on the recognition of those patients at a higher risk of stroke. These may be elderly patients with A-IAB and several risk factors and, thus, with a high CHA 2 DS 2 -Vasc score and the presence of environmental arrhythmias., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Introduction: Patient-reported outcomes (PROs) and satisfaction endpoints are increasingly important in clinical trials and may be associated with treatment adherence. In this post hoc substudy from ROCKET AF, we examined whether patient-reported satisfaction was associated with study drug discontinuation., Methods: ROCKET AF (n = 14,264) compared rivaroxaban with warfarin for prevention of stroke and systemic embolism in patients with atrial fibrillation. We analyzed treatment satisfaction scores: the Anti-Clot Treatment Scale (ACTS) and Treatment Satisfaction Questionnaire for Medication version II (TSQM II). We compared satisfaction with study drug between the two treatment arms, and examined the association between satisfaction and patient-driven study drug discontinuation (stopping study drug due to withdrawal of consent, noncompliance, or loss to follow-up)., Results: A total of 1577 (11%) patients participated in the Patient Satisfaction substudy; 1181 (8.3%) completed both the ACTS and TSQM II 4 weeks after starting study drug. Patients receiving rivaroxaban did not experience significant differences in satisfaction compared with those receiving warfarin. During a median follow-up of 1.6 years, 448 premature study drug discontinuations occurred (213 rivaroxaban group; 235 warfarin group), of which 116 (26%) were patient-driven (52 [24%] rivaroxaban group; 64 [27%] warfarin group). No significant differences were observed between satisfaction level and rates of patient-driven study drug discontinuation., Conclusions: Study drug satisfaction did not predict rate of study drug discontinuation. No significant difference was observed between satisfaction with warfarin and rivaroxaban, as expected given the double-blind trial design. Although these results are negative, the importance of PRO data will only increase, and these analyses may inform future studies that explore the relationship between drug-satisfaction PROs, adherence, and clinical outcomes. CLINICALTRIALS.GOV: NCT00403767., Funding: The ROCKET AF trial was funded by Johnson & Johnson and Bayer.

Aims: The management of anticoagulation therapy in patients with atrial fibrillation (AF) and cancer is challenging due to increased thrombotic and bleeding risks. We sought to determine the safety and efficacy of rivaroxaban in patients with AF and a history of cancer., Methods and Results: ROCKET AF randomized 14 264 patients with AF to rivaroxaban or warfarin with a median follow-up of 1.9 years. Cox regression models were used to assess the association between cancer history and clinical outcomes, and the relative treatment effect of rivaroxaban vs. warfarin in these patients. A total of 640 patients enrolled in ROCKET AF had a history of cancer, with the most common types being prostate (28.6%), colorectal (16.1%), and breast (14.7%) cancer. Patients with a history of cancer were older, more frequently male, more likely to have prior vitamin K antagonist (VKA) use and had higher rates of overall bleeding [hazard ratio (HR) 1.30, 95% confidence interval (CI) 1.16-1.47; P < 0.0001] and non-cardiovascular death (HR 1.47, 95% CI 1.04-2.07; P = 0.031) compared with those with no cancer history. There were no significant associations between cancer history and stroke, venous thromboembolism, or myocardial infarction. The relative efficacy of rivaroxaban vs. warfarin for prevention of stroke/systemic embolism was similar in those with and without a history of cancer (interaction P-value = 0.21)., Conclusion: In ROCKET AF, a history of cancer was associated with a higher risk of bleeding and non-cardiovascular death, but not ischaemic events. The relative efficacy and safety of rivaroxaban compared with warfarin were not significantly different in patients with and without a history of cancer. The results of this study are exploratory and should be taken in context of the study population, which may not be generalizable to those with advanced malignancy. Further investigation is needed to understand optimal anticoagulation strategies in patients with AF and cancer.Clinical trial registration: ClinicalTrials.gov: NCT00403767., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2018. For permissions, please email: journals.permissions@oup.com.)

Chronic kidney disease (CKD) is an independent risk factor for onset and progression of coronary artery disease (CAD). Discovery of predisposing loci for kidney function in CAD patients was performed using a genome-wide association approach. Inclusion criteria were CAD with ≥50% stenosis (≥1 coronary artery) and a creatinine-based estimated glomerular filtration rate (eGFR) of 30-75 ml/min/1.73 m 2 . An association of rs139401390 located to a region 58.8 kb upstream of renalase (RNLS) with eGFR was detected in the Ludwigshafen Risk and Cardiovascular Health (LURIC) study (n = 499, p = 7.88 × 10 -9 , mean eGFR 60.7 ml/min/1.73 m 2 ). Direct genotyping of rs139401390A > G suggested increased eGFR by 12.0 ml/min/1.73 m 2 per A allele (p = 0.000004). Genome-wide replication of rs139401390A > G in the Coronary Artery Disease and Renal Failure (CAD-REF) registry with a mean eGFR of 47.8 ml/min/1.73 m 2 (n = 574, p = 0.033) was only nominally significant. Comparison of rs139401390 genotypes for risk of reduced kidney function in the overall LURIC study revealed higher adjusted odds ratios (OR) for eGFR <60 ml/min/1.73 m 2 for CAD patients (n = 1992, OR = 2.36, p = 0.008, G/A + G/G vs A/A) compared to patients with/without CAD (n = 2908, OR = 1.97, p = 0.014, G/A + G/G vs A/A). No significant risk elevation was detected in patients without CAD (n = 948, p = 0.571). rs139401390 may affect kidney function in CAD patients with mild reduction in eGFR.

Introduction: Patients with end-stage kidney disease requiring maintenance haemodialysis treatment experience a dramatic cardiovascular morbidity and mortality. Due to the high atherosclerotic and arteriosclerotic burden and profound alterations in haemostasis, they frequently suffer and die from both thromboembolic and bleeding events. This is a particular concern in patients on haemodialysis with atrial fibrillation (AF). Controlled trials on the optimal anticoagulation in patients with AF on haemodialysis are not available. The randomised controlled phase IIIb AXADIA-AFNET 8 trial will evaluate the safety and efficacy of the factor Xa inhibitor apixaban in patients with AF requiring haemodialysis., Methods and Analysis: A total of 222 patients will be randomised in an open-labelled, 1:1 design to receive either apixaban 2.5 mg twice daily or dose-adjusted vitamin K antagonist therapy (target international normalised ratio 2.0-3.0). All patients will be treated and followed up for a minimum of 6 months up to a maximum of 24 months. The primary outcome is major or clinically relevant, non-major bleedings or death of any cause. Secondary outcomes include stroke, cardiovascular death and other thromboembolic events, thus exploring the efficacy of apixaban. The first patient was randomised in June 2017., Ethics and Dissemination: The study protocol was approved by the Ethical Committee of the Landesaertzekammer, Westfalen-Lippe and the Medical Faculty of the University of Muenster, Muenster, Germany (reference number: 2016-598 f-A). Written informed consent will be obtained from all patients prior to study participation, including their consent for long-term follow-up. AXADIA-AFNET 8 is an investigator-initiated trial. Sponsor is AFNET, Muenster, Germany. Study findings will be disseminated to Bristol-Myers Squibb, Munich, Germany, and Pfizer, Berlin, Germany, to the participating centres, at research conferences and in peer-reviewed journals., Trial Registration Numbers: NCT02933697,Pre-results., Competing Interests: Competing interests: HR has received speaker honoraria from BMS, MedUpdate, NephroUpdate, and Pfizer. He has acted as a consultant for BMS, Pfizer and Pluristem receiving in part also financial compensations for this work. He has received research grants from the German Federal Ministry for Education and Research (BMBF). His division within the University Hospital of Muenster has taken or is still taking part in multicentre trials of BARD, Bayer, BIOTRONIK, and Pluristem receiving patient fees and financial compensation for these efforts. PK has received grants and non-financial support from the European Union, British Heart Foundation, Leducq Foundation, Medical Research Council (UK), and German Centre for Cardiovascular Research and from several drug and device companies active in atrial fibrillation, and has received honoraria from several such companies. He is listed as inventor on two patents held by the University of Birmingham (Atrial Fibrillation Therapy WO 2015140571, Markers for Atrial Fibrillation WO 2016012783). During preparation of this trial, GB has received speaker honoraria from BMS and Pfizer, he has been a member of the Scientific Advisory Boards for BMS and Pfizer, and Bayer Health Care. During his chairmanship of the Atrial Fibrillation NETwork, this institution has received funding for investigator-initiated trials from various companies (for details, please consult http://www.kompetenznetz-vorhofflimmern.de/en/research). RB has received consulting / lecture fees from Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, and Pfizer. CW does not report conflicts of interest in respect to the present work. Outside this area of research he has received speaker honoraria from Amgen, Boehringer-Ingelheim, Genzyme-Sanofi and Shire., (© Author(s) (or their employer(s)) 2018. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Hypertension is a risk factor for both progression of atrial fibrillation (AF) and development of AF-related complications, that is major adverse cardiac and cerebrovascular events (MACCE). It is unknown whether left ventricular hypertrophy (LVH) as a consequence of hypertension is also a risk factor for both these end points. We aimed to assess this in low-risk AF patients, also assessing gender-related differences. We included 799 patients from the Euro Heart Survey with nonvalvular AF and a baseline echocardiogram. Patients with and without hypertension were included. End points after 1 year were occurrence of AF progression, that is paroxysmal AF becoming persistent and/or permanent AF, and MACCE. Echocardiographic LVH was present in 33% of 379 hypertensive patients. AF progression after 1 year occurred in 10.2% of 373 patients with rhythm follow-up. In hypertensive patients with LVH, AF progression occurred more frequently as compared with hypertensive patients without LVH (23.3% vs 8.8%, p = 0.011). In hypertensive AF patients, LVH was the most important multivariably adjusted determinant of AF progression on multivariable logistic regression (odds ratio 4.84, 95% confidence interval 1.70 to 13.78, p = 0.003). This effect was only seen in male patients (27.5% vs 5.8%, p = 0.002), while in female hypertensive patients, no differences were found in AF progression rates regarding the presence or absence of LVH (15.2% vs 15.0%, p = 0.999). No differences were seen in MACCE for hypertensive patients with and without LVH. In conclusion, in men with hypertension, LVH is associated with AF progression. This association seems to be absent in hypertensive women., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

Background There is concern that selective serotonin reuptake inhibitors ( SSRI s) substantially increase bleeding risk in patients taking anticoagulants. Methods and Results We studied 737 patients taking SSRI s in the ROCKET AF (Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Embolism and Stroke Trial in Atrial Fibrillation) trial of rivaroxaban compared with warfarin for the prevention of stroke/systemic embolism in patients with atrial fibrillation. These patients were propensity score matched 1:1 to 737 patients not taking SSRI s. The primary outcome measure was major and nonmajor clinically relevant bleeding events, the principal safety outcome in ROCKET AF . Over a mean 1.6 years of follow-up, the rate of major/ nonmajor clinically relevant bleeding was 18.57 events/100 patient-years for SSRI users versus 16.84 events/100 patient-years for matched comparators, adjusted hazard ratio ( aHR ) of 1.16 (95% confidence interval [CI], 0.95-1.43). The aHR s were similar in patients taking rivaroxaban ( aHR 1.11 [95% CI, 0.82-1.51]) and those taking warfarin ( aHR 1.21 [95% CI, 0.91-1.60]). For the rarer outcome of major bleeding, the aHR for SSRI users versus those not taking SSRI s was 1.13 (95% CI, 0.62-2.06) for rivaroxaban; for warfarin, the aHR was higher, at 1.58 (95% CI , 0.96-2.60) but not statistically significantly elevated. Conclusions We found no significant increase in bleeding risk when SSRI s were combined with anticoagulant therapy, although there was a suggestion of increased bleeding risk with SSRI s added to warfarin. While physicians should be vigilant regarding bleeding risk, our results provide reassurance that SSRI s can be safely added to anticoagulants in patients with atrial fibrillation . Clinical Trial Registration URL : https://www.clinicaltrials.gov . Unique identifier: NCT 00403767.

Aims: Progression of atrial fibrillation (AF) from paroxysmal to persistent forms is an active field of research. The influence of AF progression on health related quality of life (HRQoL) is currently unknown. We aimed to assess the influence of AF progression on HRQoL, and whether this association is mediated through symptoms, treatment, and major adverse events., Methods and Results: In the Euro Heart Survey, 967 patients were included with paroxysmal AF who filled out EuroQoL-5D at baseline and at 1 year follow-up. Those who progressed (n = 132, 13.6%) developed more problems during follow-up than those who did not, on all EuroQoL-5D domains (increase in problems on mobility 20.5% vs. 11.4%; self-care 12.9% vs. 6.2%; usual activities 23.5% vs. 14.0%; pain/discomfort 20.5% vs. 13.7%; and anxiety/depression 22.7% vs. 15.7%; all P < 0.05), leading to a decrease in utility [baseline 0.744 ± 0.26, follow-up 0.674 ± 0.36; difference -0.07 (95% CI [-0.126,-0.013], P = 0.02)]. Multivariate analysis showed that the effect of progression on utility is mediated by a large effect of adverse events [stroke (-0.27 (95% CI [-0.43,-0.11]); P = 0.001], heart failure [-0.12 (95% CI [-0.20,-0.05]); P = 0.001], malignancy (-0.31 (95% CI [-0.56,-0.05]); P = 0.02] or implantation of an implantable cardiac defibrillator [-0.12 (95% CI [-0.23,-0.02]); P = 0.03)], as well as symptomatic AF [-0.04 (95% CI [-0.08,-0.01]); P = 0.008]., Conclusion: AF progression is associated with a decrease in HRQoL. However, multivariate analysis revealed that AF progression itself does not have a negative effect on HRQoL, but that this effect can be attributed to a minor effect of the associated symptoms and a major effect of associated adverse events.

Background: We investigated the impact of polyvascular disease in patients enrolled in ROCKET AF., Methods: Cox regression models were used to assess clinical outcomes and treatment effects of rivaroxaban compared with warfarin in patients with atrial fibrillation and coronary, peripheral, or carotid artery disease, or any combination of the 3., Results: A total of 655 (4.6%) patients had polyvascular disease (≥2 disease locations), and 3,391 (23.8%) had single-arterial bed disease. Patients with polyvascular disease had similar rates of stroke/systemic embolism but higher rates of cardiovascular and bleeding events when compared with those without vascular disease. Use of rivaroxaban compared with warfarin was associated with higher rates of stroke in patients with polyvascular disease (hazard ratio [HR] 2.41, 95% CI 1.05-5.54); however, this was not seen in patients with single-bed (HR 0.90, 95% CI 0.64-1.28) or no vascular disease (HR 0.85, 95% CI 0.69-1.04; interaction P = .058). There was a significant interaction for major or nonmajor clinically relevant bleeding in patients with polyvascular (HR 1.23, 95% CI 0.91-1.65) and single-bed vascular disease (HR 1.30, 95% CI 1.13-1.49) treated with rivaroxaban compared with warfarin when compared with those without vascular disease (HR 0.95, 95% CI 0.87-1.04; interaction P = .0006). Additional antiplatelet therapy in this population did not improve stroke or cardiovascular outcomes., Conclusion: The use of rivaroxaban compared with warfarin was associated with a higher risk of stroke and bleeding in patients with polyvascular disease enrolled in ROCKET AF. Further studies are needed to understand the optimal management of this high-risk population., (Copyright © 2018 Elsevier Inc. All rights reserved.)