Cost-effectiveness of early rhythm control vs. usual care in atrial fibrillation care: an analysis based on data from the EAST-AFNET 4 trial.

AIMS: The randomized, controlled EAST-AFNET 4 trial showed that early rhythm control (ERC) reduces the rate of a composite primary outcome (cardiovascular death, stroke, or hospitalization for worsening heart failure or acute coronary syndrome) by ∼20%. The current study examined the cost-effectiveness of ERC compared to usual care. METHODS AND RESULTS: This within-trial cost-effectiveness analysis was based on data from the German subsample of the EAST-AFNET 4 trial (n = 1664/2789 patients). Over a 6-year time horizon and from a healthcare payer's perspective, ERC was compared to usual care regarding costs (hospitalization and medication) and effects (time to primary outcome; years survived). Incremental cost-effectiveness ratios (ICERs) were calculated. Cost-effectiveness acceptability curves were constructed to visualize uncertainty. Early rhythm control was associated with higher costs [+€1924, 95% CI (-€399, €4246)], resulting in ICERs of €10 638 per additional year without a primary outcome and €22 536 per life year gained. The probability of ERC being cost-effective compared to usual care was ≥95% or ≥80% at a willingness-to-pay value of ≥€55 000 per additional year without a primary outcome or life year gained, respectively. CONCLUSION: From a German healthcare payer's perspective, health benefits of ERC may come at reasonable costs as indicated by the ICER point estimates. Taking statistical uncertainty into account, cost-effectiveness of ERC is highly probable at a willingness-to-pay value of ≥€55 000 per additional life year or year without a primary outcome. Future studies examining the cost-effectiveness of ERC in other countries, subgroups with higher benefit from rhythm control therapy, or cost-effectiveness of different modes of ERC are warranted.

Atrial function in paroxysmal AF patients with and without heart failure with preserved ejection fraction: Data from the AF-RISK study.

Atrial fibrillation (AF) and heart failure with preserved ejection fraction (HFpEF) are 2 cardiovascular conditions that often coexist. Strain phases of both the left and right atria are more impaired in paroxysmal AF patients with HFpEF than those without HFpEF in spite of comparable global longitudinal strain of the left ventricle. Atrial function may differentiate paroxysmal AF patients with HFpEF from those without HFpEF.

Endomysial fibrosis, rather than overall connective tissue content, is the main determinant of conduction disturbances in human atrial fibrillation.

AIMS: Although in persistent atrial fibrillation (AF) a complex AF substrate characterized by a high incidence of conduction block has been reported, relatively little is known about AF complexity in paroxysmal AF (pAF). Also, the relative contribution of various aspects of structural alterations to conduction disturbances is not clear. In particular, the contribution of endomysial fibrosis to conduction disturbances during progression of AF has not been studied yet. METHODS AND RESULTS: During cardiac surgery, epicardial high-density mapping was performed in patients with acutely induced (aAF, n = 11), pAF (n = 12), and longstanding persistent AF (persAF, n = 9) on the right atrial (RA) wall, the posterior left atrial wall (pLA) and the LA appendage (LAA). In RA appendages, overall and endomysial (myocyte-to-myocyte distances) fibrosis and connexin 43 (Cx43) distribution were quantified. Unipolar AF electrogram analysis showed a more complex pattern with a larger number of narrower waves, more breakthroughs and a higher fractionation index (FI) in persAF compared with aAF and pAF, with no differences between aAF and pAF. The FI was consistently higher at the pLA compared with the RA. Structurally, Cx43 lateralization increased with AF progression (aAF = 7.5 ± 8.9%, pAF = 24.7 ± 11.1%, persAF = 35.1 ± 11.4%, P < 0.001). Endomysial but not overall fibrosis correlated with AF complexity (r = 0.57, P = 0.001; r = 0.23, P = 0.20; respectively). CONCLUSIONS: Atrial fibrillation complexity is highly variable in patients with pAF, but not significantly higher than in patients with acutely induced AF, while in patients with persistent AF complexity is higher. Among the structural alterations studied, endomysial fibrosis, but not overall fibrosis, is the strongest determinant of AF complexity.

Rate control in atrial fibrillation, calcium channel blockers versus beta-blockers.

OBJECTIVE: To investigate heart rate differences between non-dihydropyridine calcium channel blockers and beta-blockers in patients with non-permanent atrial fibrillation (AF). METHODS: Using data from 'A Comparison of Rate Control and Rhythm Control in Patients with Atrial Fibrillation' (AFFIRM), where patients were randomised 1:1 rate or rhythm control, we compared the effect of rate control drugs on heart rate during AF as well as during sinus rhythm. Multivariable logistic regression was used to adjust for baseline characteristics. RESULTS: A total of 4060 patients were enrolled in the AFFIRM trial, mean age was 70±9 years, 39% were women. Out of the total, 1112 patients were in sinus rhythm at baseline and used either non-dihydropyridine channel blockers or beta-blockers. Of them, 474 had AF during follow-up while remaining on the same rate control drugs, 218 (46%) on calcium channel blockers and 256 (54%) on beta-blockers. Mean age of calcium channel blocker patients was 70±8 years and 68±8 for beta-blocker patients (p=0.003), 42% were women. A resting heart rate <110 beats per min during AF was achieved in 92% of patients using calcium channel blockers and 92% of patients using beta-blockers (p=1.00). Bradycardia during sinus rhythm occurred in 17% of patients using calcium channel blockers vs 32% using beta-blockers (p<0.001). After adjusting for patient characteristics, calcium channel blockers were associated with a reduction in bradycardia during sinus rhythm (OR 0.41, 95% CI 0.19 to 0.90). CONCLUSION: In patients with non-permanent AF, calcium channel blockers instituted for rate control were associated with less bradycardia during sinus rhythm compared with beta-blockers.

Prevalence and determinants of atrial fibrillation progression in paroxysmal atrial fibrillation.

OBJECTIVE: Atrial fibrillation (AF) often progresses from paroxysmal AF (PAF) to more permanent forms. To improve personalised medicine, we aim to develop a new AF progression risk prediction model in patients with PAF. METHODS: In this interim-analysis of the Reappraisal of AF: Interaction Between HyperCoagulability, Electrical Remodelling, and Vascular Destabilisation in the Progression of AF study, patients with PAF undergoing extensive phenotyping at baseline and continuous rhythm monitoring during follow-up of ≥1 year were analysed. AF progression was defined as (1) progression to persistent or permanent AF or (2) progression of PAF with >3% burden increase. Multivariable analysis was done to identify predictors of AF progression. RESULTS: Mean age was 65 (58-71) years, 179 (43%) were female. Follow-up was 2.2 (1.6-2.8) years, 51 of 417 patients (5.5%/year) showed AF progression. Multivariable analysis identified, PR interval, impaired left atrial function, mitral valve regurgitation and waist circumference to be associated with AF progression. Adding blood biomarkers improved the model (C-statistic from 0.709 to 0.830) and showed male sex, lower levels of factor XIIa:C1-esterase inhibitor and tissue factor pathway inhibitor, and higher levels of N-terminal pro-brain natriuretic peptide, proprotein convertase subtilisin/kexin type 9 and peptidoglycan recognition protein 1 were associated with AF progression. CONCLUSION: In patients with PAF, AF progression occurred in 5.5%/year. Predictors for progression included markers for atrial remodelling, sex, mitral valve regurgitation, waist circumference and biomarkers associated with coagulation, inflammation, cardiomyocyte stretch and atherosclerosis. These prediction models may help to determine risk of AF progression and treatment targets, but validation is needed. TRIAL REGISTRATION NUMBER: NCT02726698.

Frequency and Determinants of Spontaneous Conversion to Sinus Rhythm in Patients Presenting to the Emergency Department with Recent-onset Atrial Fibrillation: A Systematic Review.

The exact frequency and clinical determinants of spontaneous conversion (SCV) in patients with symptomatic recent-onset AF are unclear. The aim of this systematic review is to provide an overview of the frequency and determinants of SCV of AF in patients presenting at the emergency department. A comprehensive literature search for studies about SCV in patients presenting to the emergency department with AF resulted in 25 articles - 12 randomised controlled trials and 13 observational studies. SCV rates range between 9-83% and determinants of SCV also varied between studies. The most important determinants of SCV included short duration of AF (<24 or <48 hours), low number of episodes, normal atrial dimensions and absence of previous heart disease. The large variation in SCV rate and determinants of SCV was related to differences in duration of the observation period, inclusion and exclusion criteria and in variables used in the prediction models.

Design and rationale of DUTCH-AF: a prospective nationwide registry programme and observational study on long-term oral antithrombotic treatment in patients with atrial fibrillation.

INTRODUCTION: Anticoagulation therapy is pivotal in the management of stroke prevention in atrial fibrillation (AF). Prospective registries, containing longitudinal data are lacking with detailed information on anticoagulant therapy, treatment adherence and AF-related adverse events in practice-based patient cohorts, in particular for non-vitamin K oral anticoagulants (NOAC). With the creation of DUTCH-AF, a nationwide longitudinal AF registry, we aim to provide clinical data and answer questions on the (anticoagulant) management over time and of the clinical course of patients with newly diagnosed AF in routine clinical care. Within DUTCH-AF, our current aim is to assess the effect of non-adherence and non-persistence of anticoagulation therapy on clinical adverse events (eg, bleeding and stroke), to determine predictors for such inadequate anticoagulant treatment, and to validate and refine bleeding prediction models. With DUTCH-AF, we provide the basis for a continuing nationwide AF registry, which will facilitate subsequent research, including future registry-based clinical trials. METHODS AND ANALYSIS: The DUTCH-AF registry is a nationwide, prospective registry of patients with newly diagnosed 'non-valvular' AF. Patients will be enrolled from primary, secondary and tertiary care practices across the Netherlands. A target of 6000 patients for this initial cohort will be followed for at least 2 years. Data on thromboembolic and bleeding events, changes in antithrombotic therapy and hospital admissions will be registered. Pharmacy-dispensing data will be obtained to calculate parameters of adherence and persistence to anticoagulant treatment, which will be linked to AF-related outcomes such as ischaemic stroke and major bleeding. In a subset of patients, anticoagulation adherence and beliefs about drugs will be assessed by questionnaire. ETHICS AND DISSEMINATION: This study protocol was approved as exempt for formal review according to Dutch law by the Medical Ethics Committee of the Leiden University Medical Centre, Leiden, the Netherlands. Results will be disseminated by publications in peer-reviewed journals and presentations at scientific congresses. TRIAL REGISTRATION NUMBER: Trial NL7467, NTR7706 (https://www.trialregister.nl/trial/7464).

The Biomarkers NT-proBNP and CA-125 are Elevated in Patients with Idiopathic Atrial Fibrillation.

BACKGROUND: Blood biomarkers related to AF could be useful to detect silent AF and to develop stratified strategies for AF prevention. Previous studies identified markers that predict incident AF. However, it is difficult to differentiate whether biomarkers relate to underlying cardiovascular diseases, are generated by the atria in response to an AF episode, or both. We therefore measured a panel of blood biomarkers in patients without overt CVD with and without AF to investigate the association between biomarkers and atrial fibrillation (AF) in patients without overt cardiovascular disease (CVD). METHODS: Blood samples - drawn remote from an AF episode - of 60 patients with AF but without overt forms of CVD (idiopathic AF; iAF) were compared to 120 matched patients with sinus rhythm only. A novel antibody-based method for quantification of blood biomarkers (OlinkProseek Multiplex Cardiovascular) was used to compare 92 biomarkers between the two groups. RESULTS: N-terminal pro-B-type natriuretic peptide (NT-proBNP), Cathepsin L1, Endothelial cell-specific molecule 1, Cancer Antigen-125 (CA-125), Heat shock 27kDa protein, Galanin peptides, Proteinase-activated receptor 1, Stem cell factor, and CD40-ligand were all higher in iAF patients than in SR controls. Both NT-proBNP (OR1.55(1.07-2.25);p=0.022) and CA-125 (OR1.68(1.07-2.64);p=0.026) were independently associated with iAF. CONCLUSIONS: This exploratory study, investigating over 90 cardiovascular blood biomarkers in patients without known CVD, identified one established biomarker for paroxysmal AF, NT-proBNP, and a novel marker, CA-125. CA-125 - previously unrelated to paroxysmal AF in an otherwise healthy population - may thus be a potential indicator of remote paroxysms of AF.

Poor anticoagulation relates to extended access times for cardioversion and is associated with long-term major cardiac and cerebrovascular events.

BACKGROUND: Patients undergoing elective electrical cardioversion (ECV) for atrial fibrillation have a temporarily increased risk of thromboembolism. Current guidelines recommend adequate anticoagulation for ≥3 consecutive weeks precardioversion, i.e. consecutive INR values 2.0-3.0 in patients with vitamin K antagonists (VKA). We aimed to evaluate the occurrence and impact of subtherapeutic INRs precardioversion and to study factors associated with these unwanted fluctuations. METHODS: We recruited 346 consecutive patients undergoing elective ECV in the Maastricht University Medical Centre between 2008 and 2013. Predictors of subtherapeutic INR values were identified and incorporated into a logistic regression model. RESULTS: A subtherapeutic INR precardioversion occurred in 55.2% of patients. The only statistically significant predictor was VKA-naivety (Odds Ratio (OR) 4.78, 95% Confidence Interval (CI) 2.67-8.58, p<0.001). In patients with ≥1 subtherapeutic INR precardioversion, time from referral until cardioversion was 91.1±42.8days, compared to 41.7±26.6days (p<0.001) in patients without subtherapeutic INRs. No thromboembolic events occurred <30days after the ECV. Independent predictors for the combined endpoint of cardiovascular death, ischemic stroke and the need of blood transfusion (n=30, median follow-up of 374days) were coronary artery disease in the history (OR 3.35, 95%CI 1.54-7.25, p=0.002) and subtherapeutic INR precardioversion (OR 3.64, 95%CI 1.43-9.24, p=0.007). CONCLUSIONS: The use of VKA often results in subtherapeutic INRs precardioversion and is associated with a significant delay until cardioversion, especially in patients with recent initiation of VKA therapy. Furthermore, subtherapeutic INR levels prior to ECV are associated with the combined endpoint of cardiovascular death, ischemic stroke and the need of blood transfusion.

Integrated Chronic Care Management For Patients With Atrial Fibrillation - A Rationale For Redesigning Atrial Fibrillation Care.

Atrial Fibrillation (AF) is a highly prevalent heart rhythm disturbance, often associated with underlying (cardio)vascular disease. Due to this the management of AF is often complex and current practice calls for a more comprehensive, multifactorial and patient-centred approach. Therefore an Integrated Chronic Care approach in AF was developed and implemented in terms of a nurse-led specialized outpatient clinic for patients with AF. A randomised controlled trial comparing the nurse-led approach with usual care demonstrated superiority in terms of cardiovascular hospitalization and death as well as cost-effectiveness in terms of Quality Adjusted Life Years (QALYs) and life years, in favour of the nurse-led approach. Implementing such approach can be difficult since daily practice can be persistent. To highlight the importance of integrated care wherein the nurse fulfils a significant role, and to provide a guide in developing and continuing such approach, this paper presents the theoretical framework of the AF-Clinic based on the principles of the Taxonomy for Integrated Chronic Atrial Fibrillation Management.