Current Anticoagulant Usage Patterns and Determinants in Korean Patients with Nonvalvular Atrial Fibrillation

PURPOSE: Stroke prevention in patients with atrial fibrillation (AF) is influenced by many factors. Using a contemporary registry, we evaluated variables associated with the use of warfarin or direct oral anticoagulants (OACs). MATERIALS AND METHODS: In the prospective multicenter CODE-AF registry, 10529 patients with AF were evaluated. Multivariate analyses were performed to identify variables associated with the use of anticoagulants. RESULTS: The mean age of the patients was 66.9±14.4 years, and 64.9% were men. The mean CHA₂DS₂-VASc and HAS-BLED scores were 2.6±1.7 and 1.8±1.1, respectively. In patients with high stroke risk (CHA₂DS₂-VASc ≥2), OACs were used in 83.2%, including direct OAC in 68.8%. The most important factors for non-OAC treatment were end-stage renal disease [odds ratio (OR) 0.27; 95% confidence interval (CI): 0.19-0.40], myocardial infarct (OR 0.53; 95% CI: 0.40-0.72), and major bleeding (OR 0.57; 95% CI: 0.39-0.84). Female sex (OR 1.40; 95% CI: 1.21-1.61), cancer (OR 1.78; 95% CI: 1.38-2.29), and smoking (OR 1.60; 95% CI: 1.15-2.24) were factors favoring direct OAC use over warfarin. Among patients receiving OACs, the rate of combined antiplatelet agents was 7.8%. However, 73.6% of patients did not have any indication for a combination of antiplatelet agents. CONCLUSION: Renal disease and history of valvular heart disease were associated with warfarin use, while cancer and smoking status were associated with direct OAC use in high stroke risk patients. The combination of antiplatelet agents with OAC was prescribed in 73.6% of patients without definite indications recommended by guidelines.ope

Physical Activity and Risk of Atrial Fibrillation: A Nationwide Cohort Study in General Population

Although exercise prevents cardiovascular disease and mortality, vigorous exercise and endurance athletics can cause atrial fibrillation (AF). However, no large cohort study has assessed the relationship between physical activity and AF in the general population. We assessed the effect of physical activity at different energy expenditures on the incidence of AF. We studied 501,690 individuals without pre-existing AF (mean age, 47.6 ± 14.3 years; 250,664 women [50.0%]) included in the Korean National Health Insurance Service database. The physical activity level was assessed using a standardized self-reported questionnaire at baseline. During a median follow-up of 4 years, 3,443 participants (1,432 women [41.6%]) developed AF. The overall incidence of AF at follow-up was 1.79 per 1,000 person-years. The subjects who met the recommended physical activity level (500-1,000 metabolic equivalent task [MET] minutes/week) had a 12% decreased AF risk (adjusted hazard ratio [HR]: 0.88, 95% confidence interval [CI]: 0.80-0.97), but not the insufficiently (1-500 MET-minutes/week; HR: 0.94, 95% CI: 0.86-1.03) and highly active subjects (≥1,000 MET-minutes/week; HR: 0.93, 95% CI: 0.85-1.03). The recommended minimum key target range of physical activity level was associated with the maximum benefit for reduced AF risk in the general population. The dose-response relationship between physical activity level and AF risk showed a U-shaped pattern. Although exceeding the key target range attenuated this benefit, it did not increase the AF risk beyond that during inactivity.ope

Cost-Effectiveness of Rate- and Rhythm-Control Drugs for Treating Atrial Fibrillation in Korea

PURPOSE: Although the economic and mortality burden of atrial fibrillation (AF) is substantial, it remains unclear which treatment strategies for rate and rhythm control are most cost-effective. Consequently, economic factors can play an adjunctive role in guiding treatment selection. MATERIALS AND METHODS: We built a Markov chain Monte Carlo model using the Korean Health Insurance Review & Assessment Service database. Drugs for rate control and rhythm control in AF were analyzed. Cost-effective therapies were selected using a cost-effectiveness ratio, calculated by net cost and quality-adjusted life years (QALY). RESULTS: In the National Health Insurance Service data, 268149 patients with prevalent AF (age ≥18 years) were identified between January 1, 2013 and December 31, 2015. Among them, 212459 and 55690 patients were taking drugs for rate and rhythm control, respectively. Atenolol cost $714/QALY. Among the rate-control medications, the cost of propranolol was lowest at$487/QALY, while that of carvedilol was highest at $1363/QALY. Among the rhythm-control medications, the cost of pilsicainide was lowest at$638/QALY, while that of amiodarone was highest at $986/QALY. Flecainide and propafenone cost$834 and $830/QALY, respectively. The cost-effectiveness threshold of all drugs was lower than$30000/QALY. Compared with atenolol, the rate-control drugs propranolol, betaxolol, bevantolol, bisoprolol, diltiazem, and verapamil, as well as the rhythm-control drugs sotalol, pilsicainide, flecainide, propafenone, and dronedarone, showed better incremental cost-effectiveness ratios. CONCLUSION: Propranolol and pilsicainide appear to be cost-effective in patients with AF in Korea assuming that drug usage or compliance is the same.ope

Catheter Ablation of Atrial Fibrillation Raises the Plasma Level of NGF-β Which Is Associated with Sympathetic Nerve Activity

PURPOSE: The expression of nerve growth factor-β (NGF-β) is related to cardiac nerve sprouting and sympathetic hyper innervation. We investigated the changes of plasma levels of NGF-β and the relationship to follow-up heart rate variability (HRV) after radiofrequency catheter ablation (RFCA) of atrial fibrillation (AF). MATERIALS AND METHODS: This study included 147 patients with AF (117 men, 55.8±11.5 years, 106 paroxysmal AF) who underwent RFCA. The plasma levels of NGF-β were quantified using double sandwich enzyme linked immunosorbent assay method before (NGF-β(pre)) and 1 hour after RFCA (NGF-β(post-1hr)). HRV at pre-procedure (HRV(pre)), 3 months (HRV(post-3mo)), and 1 year post-procedure (HRV(post-1yr)) were analyzed and compared with plasma levels of NGF-β. RESULTS: 1) The plasma levels of NGF-β significantly increased after RFCA (20.05±11.09 pg/mL vs. 29.60±19.43 pg/mL, p18 pg/mL, low frequency components (LF)/high-frequency components (HF) (p=0.003) and the number of atrial premature contractions (APCs, p=0.045) in HRV(post-3mo) were significantly higher than those with ≤18 pg/mL. 3) The LF/HF at HRV(post-3mo) was linearly associated with the NGF-β(pre) (B=4.240, 95% CI 1.114-7.336, p=0.008) and the NGF-β(post-1hr) (B=7.617, 95% CI 2.106-13.127, p=0.007). 4) Both NGF-β(pre) (OR=1.159, 95% CI 1.045-1.286, p=0.005) and NGF-β(post-1hr) (OR=1.098, 95% CI 1.030-1.170, p=0.004) were independent predictors for the increase of LF/HF at HRV(post-3mo). CONCLUSION: AF catheter ablation increases plasma level of NGF-β, and high plasma levels of NGF-β(pre) was associated with higher sympathetic nerve activity and higher frequency of APCs in HRV(post-3mo).ope

Association of Gender With Clinical Outcomes in a Contemporary Cohort of Patients With Atrial Fibrillation Receiving Oral Anticoagulants

Background and objectives: In patients with atrial fibrillation (AF), females taking vitamin K antagonist are at higher risk of stroke or systemic embolism (SSE), bleeding and all-cause death than males. This study investigated the relationship between sex and adverse clinical events in a contemporary AF patient cohort taking anticoagulation. Methods: This prospective multicenter AF registry study comprised 6,067 patients with AF (mean age, 70±9 years; men, 59%) with intermediate to high risk of stroke (CHA2DS2-VAscore ≥1) and receiving oral anticoagulation therapy. Adverse clinical outcomes, including SSE, bleeding, death were evaluated in patients stratified by sex and anticoagulation patterns. Results: Women were older and used more direct oral anticoagulants (85% vs. 78%, p<0.001) than men. During a median (25th and 75th percentiles) follow-up of 30 (24, 38) months, the incidence rate and risk of SSE (0.7 in women vs. 0.7 in men per 100 person-years) and major bleeding (0.1 in women vs. 0.1 in men per 100 person-years) were not different between the sexes. However, women had a lower all-cause death rate (0.4 in women vs. 0.6 in men per 100 person-years, hazard ratio: 0.48, 95% confidence interval: 0.25-0.91, p=0.025) than men. Conclusions: In contemporary anticoagulation for AF, SSE and major bleeding risks did not differ between sexes. However, women showed a lower risk of all-cause death rate than men, indicating that the use of oral anticoagulants for treating AF in females does not appear to be a risk factor for adverse clinical events. Trial registration: ClinicalTrials.gov Identifier: NCT02786095.ope

Conduit Puncture for Electrophysiological Procedures in Patients with Fontan Circulation

Background: Electrophysiological procedures are challenging in patients who have undergone lateral tunnel or extracardiac conduit Fontan operation because the caval veins are not connected to the cardiac atria and ventricles. This study describes our experience in managing a series of patients with Fontan circulation requiring catheter ablation for arrhythmias. Methods: This study included eight consecutive patients with Fontan circulation who underwent catheter ablation or pacemaker implantation via Fontan conduit puncture [median age (interquartile range), 21.5 (16.0-25.8) years; 5 men]. Lateral tunnel and extracardiac conduit were equally distributed among the eight patients. A standard technique for conduit puncture and subsequent electrophysiologic procedure was used. The time taken for conduit puncture was compared for different types of conduits. Results: The median age of patients in this series was 21.5 years (interquartile range: 16.0-25.8 years). Fontan conduit puncture via right femoral vein under intracardiac echocardiographic guidance was successfully performed without complications in seven of the eight patients. Conduit puncture failed in one patient with extracardiac conduit made of the pericardium due to interruption of both femoral veins. In three patients with Fontan conduit made of pericardium, a Bronckenbrough transseptal needle or a radiofrequency transseptal needle with a snare was used. In four patients with Fontan conduit made of Gore-tex, a radiofrequency transseptal needle with a snare, and percutaneous transluminal angioplasty balloon were used. Fontan conduit puncture time was significantly longer in patients with conduit made of Gore-tex (median time, 91 min; interquartile range, 59.8-130.5 min) than in patients with conduit made of the pericardium (median time, 11.5 min; interquartile range, 10.0-18.3 min), respectively (p=0.020). Conclusions: Conduit puncture is feasible and safe in patients with lateral tunnel and extracardiac Fontan circulation. Puncture of the Gore-tex conduit is more difficult and time consuming than puncture of the pericardium conduit.ope

Real-world Data and Recommended Dosage of Non-vitamin K Oral Anticoagulants for Korean Patients

Regulatory approvals of non-vitamin K antagonist oral anticoagulants (NOACs) have been based on large randomized phase III trials evaluating dabigatran, rivaroxaban, apixaban, or edoxaban relative to warfarin for atrial fibrillation (AF). The results of the trials showed that all NOACs were at least non-inferior to warfarin in the prevention of stroke/thromboembolism and showed lower rates of intracranial bleeding than those associated with warfarin. However, the trials were designed differently, varied in the inclusion/exclusion criteria, and used either one dose or a low/high dose of the NOAC drug. Some of these differences have challenged the ability to directly compare various NOACs, and comparative data on effectiveness and intracranial bleeding are sparse in "real-world" patients. Real-world data complement data from large randomized phase III trials by providing new aspects of the "real-world" absolute risks of ischemic and hemorrhagic stroke associated with NOACs vs. warfarin. Moreover, "real-world" fragile patients might have been included (e.g., patients with increased risk of bleeding, liver disease, and chronic kidney disease), although these patients would be less represented in trials. This paper introduces recently published real-world data of NOACs and further suggests the recommended dosage of NOACs for Korean patients.ope

The role of the calcium and the voltage clocks in sinoatrial node dysfunction

Recent evidence indicates that the voltage clock (cyclic activation and deactivation of membrane ion channels) and Ca(2+) clocks (rhythmic spontaneous sarcoplasmic reticulum Ca(2+) release) jointly regulate sinoatrial node (SAN) automaticity. However, the relative importance of the voltage clock and Ca(2+) clock for pacemaking was not revealed in sick sinus syndrome. Previously, we mapped the intracellular calcium (Ca(i)) and membrane potentials of the normal intact SAN simultaneously using optical mapping in Langendorff-perfused canine right atrium. We demonstrated that the sinus rate increased and the leading pacemaker shifted to the superior SAN with robust late diastolic Ca(i) elevation (LDCAE) during β-adrenergic stimulation. We also showed that the LDCAE was caused by spontaneous diastolic sarcoplasmic reticulum (SR) Ca(2+) release and was closely related to heart rate changes. In contrast, in pacing induced canine atrial fibrillation and SAN dysfunction models, Ca(2+) clock of SAN was unresponsiveness to β-adrenergic stimulation and caffeine. Ryanodine receptor 2 (RyR2) in SAN was down-regulated. Using the prolonged low dose isoproterenol together with funny current block, we produced a tachybradycardia model. In this model, chronically elevated sympathetic tone results in abnormal pacemaking hierarchy in the right atrium, including suppression of the superior SAN and enhanced pacemaking from ectopic sites. Finally, if the LDCAE was too small to trigger an action potential, then it induced only delayed afterdepolarization (DAD)-like diastolic depolarization (DD). The failure of DAD-like DD to consistently trigger a sinus beat is a novel mechanism of atrial arrhythmogenesis. We conclude that dysfunction of both the Ca(2+) clock and the voltage clock are important in sick sinus syndrome.ope

Antithrombotic Medication and the Risk of Vitreous Hemorrhage in Atrial Fibrillation: Korean National Health Insurance Service National Cohort

Purpose: Antithrombotic therapy could be related with nuisance bleeding. This study investigated whether vitreous hemorrhage (VH) is associated with specific types of antithrombotic medication in patients with atrial fibrillation (AF). Materials and Methods: In the Korean National Health Insurance Service National Sample Cohort, we identified 9352 antiplatelet/ anticoagulant-treated AF patients. The occurrence of VH was compared between warfarin (n=1493) and a propensity score (PS)matched antiplatelet group (n=1493) and between warfarin (n=1493) and a PS-matched warfarin+antiplatelet group (n=1493). Results: The outcomes of VH were lower in the warfarin than in the matched antiplatelet (1.45 vs. 3.72 events/1000 patient-years) and matched warfarin+antiplatelet groups (1.45 vs. 6.87 events/1000 patient-years). Compared with warfarin, the risk of VH increased with antiplatelet [adjusted hazard ratio (aHR) 3.90; 95% confidence interval (CI) 1.22–12.4, p=0.022] and warfarin+antiplatelet agents (aHR 4.39, 95% CI 1.74–11.2, p=0.002). Compared with warfarin only, warfarin+antiplatelet agents increased the risk of VH in patients ≥65 years, regardless of gender and hypertension. The risk of VH was significantly higher with dual antiplatelet therapy (aHR: 5.02, 95% CI: 1.56–16.2, p=0.007) or in dual (aHR: 5.02, 95% CI: 1.74–14.5, p=0.003) or triple therapy using warfarin and antiplatelet agents than with warfarin monotherapy (aHR: 6.12, 95% CI: 1.76–21.3, p=0.004). Conclusion: Dual antiplatelet or triple therapy increased the risk of VH significantly, compared to warfarin monotherapy. Considering the low efficacy of preventing ischemic stroke and high risk of bleeding, dual or triple therapy using warfarin and antiplatelet agents should be avoided to prevent VH in AF patients.ope

Autonomic nervous system activity measured directly and QT interval variability in normal and pacing-induced tachycardia heart failure dogs.

OBJECTIVES: This study sought to find out more about the relationship between sympathetic and vagal nerve activity and the cardiac repolarization in a canine model of pacing-induced tachycardia congestive heart failure (CHF). BACKGROUND: The QT variability index (QTVI), a noninvasive marker of temporal cardiac repolarization dispersion, is among the risk factors for sudden death during CHF. Among factors influencing this variable are the myocardial damage and the autonomic nervous system activity typical of dilated cardiomyopathy. METHODS: We assessed autonomic nervous system activity recorded from an implanted data transmitter that monitored integrated left stellate-ganglion nervous activity, integrated vagus nerve activity, and electrocardiogram. We collected 36 segments recorded at baseline and 36 after induced CHF. We then arbitrarily identified recording segments as containing low or high sympathetic activity values, and we compared corrected QT intervals and the QTVI under a given sympathetic activity condition at baseline and after inducing CHF. RESULTS: In the high sympathetic activity subgroup, both QT variables increased from baseline to CHF (corrected QT intervals, p < 0.01; QTVI, p < 0.05) whereas in the low sympathetic activity subgroup they remained unchanged. The baseline QTVI correlated inversely with integrated vagus nerve activity (r(2) = 0.16; beta = -0.47; p < 0.05) whereas, during CHF, the QTVI correlated directly with integrated left stellate-ganglion nervous activity (r(2) = 0.32; beta = 0.27, p < 0.01). CONCLUSIONS: During CHF, sympathetic activation is associated with an increase in the QT interval and QTVI. Because these changes vary over time, they could result from myocardial structural damage and sympathetic activation combined. Conversely, under normal conditions, no relationship exists between sympathetic activation and the QT variables.ope