Anticoagulation with edoxaban in patients with long atrial high-rate episodes ≥24†h.

BACKGROUND AND AIMS: Patients with long atrial high-rate episodes (AHREs) ≥24 h and stroke risk factors are often treated with anticoagulation for stroke prevention. Anticoagulation has never been compared with no anticoagulation in these patients. METHODS: This secondary pre-specified analysis of the Non-vitamin K antagonist Oral anticoagulants in patients with Atrial High-rate episodes (NOAH-AFNET 6) trial examined interactions between AHRE duration at baseline and anticoagulation with edoxaban compared with placebo in patients with AHRE and stroke risk factors. The primary efficacy outcome was a composite of stroke, systemic embolism, or cardiovascular death. The safety outcome was a composite of major bleeding and death. Key secondary outcomes were components of these outcomes and electrocardiogram (ECG)-diagnosed atrial fibrillation. RESULTS: Median follow-up of 2389 patients with core lab-verified AHRE was 1.8 years. AHRE ≥24 h were present at baseline in 259/2389 patients (11%, 78 ± 7 years old, 28% women, CHA2DS2-VASc 4). Clinical characteristics were not different from patients with shorter AHRE. The primary outcome occurred in 9/132 patients with AHRE ≥24 h (4.3%/patient-year, 2 strokes) treated with anticoagulation and in 14/127 patients treated with placebo (6.9%/patient-year, 2 strokes). Atrial high-rate episode duration did not interact with the efficacy (P-interaction = .65) or safety (P-interaction = .98) of anticoagulation. Analyses including AHRE as a continuous parameter confirmed this. Patients with AHRE ≥24 h developed more ECG-diagnosed atrial fibrillation (17.0%/patient-year) than patients with shorter AHRE (8.2%/patient-year; P < .001). CONCLUSIONS: This hypothesis-generating analysis does not find an interaction between AHRE duration and anticoagulation therapy in patients with device-detected AHRE and stroke risk factors. Further research is needed to identify patients with long AHRE at high stroke risk.

Anticoagulation with Edoxaban in Patients with Atrial High-Rate Episodes.

BACKGROUND: Device-detected atrial high-rate episodes (AHREs) are atrial arrhythmias detected by implanted cardiac devices. AHREs resemble atrial fibrillation but are rare and brief. Whether the occurrence of AHREs in patients without atrial fibrillation (as documented on a conventional electrocardiogram [ECG]) justifies the initiation of anticoagulants is not known. METHODS: We conducted an event-driven, double-blind, double-dummy, randomized trial involving patients 65 years of age or older who had AHREs lasting for at least 6 minutes and who had at least one additional risk factor for stroke. Patients were randomly assigned in a 1:1 ratio to receive edoxaban or placebo. The primary efficacy outcome was a composite of cardiovascular death, stroke, or systemic embolism, evaluated in a time-to-event analysis. The safety outcome was a composite of death from any cause or major bleeding. RESULTS: The analysis population consisted of 2536 patients (1270 in the edoxaban group and 1266 in the placebo group). The mean age was 78 years, 37.4% were women, and the median duration of AHREs was 2.8 hours. The trial was terminated early, at a median follow-up of 21 months, on the basis of safety concerns and the results of an independent, informal assessment of futility for the efficacy of edoxaban; at termination, the planned enrollment had been completed. A primary efficacy outcome event occurred in 83 patients (3.2% per patient-year) in the edoxaban group and in 101 patients (4.0% per patient-year) in the placebo group (hazard ratio, 0.81; 95% confidence interval [CI], 0.60 to 1.08; P = 0.15). The incidence of stroke was approximately 1% per patient-year in both groups. A safety outcome event occurred in 149 patients (5.9% per patient-year) in the edoxaban group and in 114 patients (4.5% per patient-year) in the placebo group (hazard ratio, 1.31; 95% CI, 1.02 to 1.67; P = 0.03). ECG-diagnosed atrial fibrillation developed in 462 of 2536 patients (18.2% total, 8.7% per patient-year). CONCLUSIONS: Among patients with AHREs detected by implantable devices, anticoagulation with edoxaban did not significantly reduce the incidence of a composite of cardiovascular death, stroke, or systemic embolism as compared with placebo, but it led to a higher incidence of a composite of death or major bleeding. The incidence of stroke was low in both groups. (Funded by the German Center for Cardiovascular Research and others; NOAH-AFNET 6 ClinicalTrials.gov number, NCT02618577; ISRCTN number, ISRCTN17309850.).

The influence of atrial high-rate episodes on stroke and cardiovascular death: an update.

Atrial high-rate episodes (AHRE) are atrial tachyarrhythmias detected by continuous rhythm monitoring by pacemakers, defibrillators, or implantable cardiac monitors. Atrial high-rate episodes occur in 10-30% of elderly patients without atrial fibrillation. However, it remains unclear whether the presence of these arrhythmias has therapeutic consequences. The presence of AHRE increases the risk of stroke compared with patients without AHRE. Oral anticoagulation would have the potential to reduce the risk of stroke in patients with AHRE but is also associated with a rate of major bleeding of ∼2%/year. The stroke rate in patients with AHRE appears to be lower than the stroke rate in patients with atrial fibrillation. Wearables like smart-watches will increase the absolute number of patients in whom atrial arrhythmias are detected. It remains unclear whether anticoagulation is effective and, equally important, safe in patients with AHRE. Two randomized clinical trials, NOAH-AFNET6 and ARTESiA, are expected to report soon. They will provide much-needed information on the efficacy and safety of oral anticoagulation in patients with AHRE.

Flecainide in clinical practice.

Flecainide, similar to encainide and propafenone, is IC class antiarrhythmic, inhibiting Nav1.5 sodium channels in heart muscle cells and modulates cardiac conduction. Despite its over 40-year presence in clinical practice, strong evidence and well-known safety profile, flecainide distribution in Europe has not always been equal. In Poland, the drug has been available in pharmacies only since October this year, and previously it had to be imported on request. Flecainide can be used successfully in both the acute and chronic treatment of cardiac arrhythmias. The main indication for flecainide is the treatment of paroxysmal supraventricular tachycardias, including atrial fibrillation, atrioventricular nodal re-entrant tachycardia, atrioventricular re-entrant tachycardia and ventricular arrhythmias in patients without structural heart disease. Beyond that, it may be used in some supraventricular tachycardia in children and for sustained fetal tachycardia. Many studies indicate its efficacy comparable to or better than previously used drugs such as propafenone and amiodarone, depending on the indication. This review aims to highlight the most important clinical uses of flecainide in the light of the latest scientific evidence and to provide an overview of the practical aspects of treatment, including indications, off-label use, contraindications, areas of use, monitoring of treatment and most common complications, taking into account special populations: children and pregnant women.

Enhancing Healthcare Access-Smartphone Apps in Arrhythmia Screening: Viewpoint.

Atrial fibrillation is the most commonly reported arrhythmia and, if undiagnosed or untreated, may lead to thromboembolic events. It is therefore desirable to provide screening to patients in order to detect atrial arrhythmias. Specific mobile apps and accessory devices, such as smartphones and smartwatches, may play a significant role in monitoring heart rhythm in populations at high risk of arrhythmia. These apps are becoming increasingly common among patients and professionals as a part of mobile health. The rapid development of mobile health solutions may revolutionize approaches to arrhythmia screening. In this viewpoint paper, we assess the availability of smartphone and smartwatch apps and evaluate their efficacy for monitoring heart rhythm and arrhythmia detection. The findings obtained so far suggest they are on the right track to improving the efficacy of early detection of atrial fibrillation, thus lowering the risk of stroke and reducing the economic burden placed on public health.

Nocturnal respiratory rate predicts ICD benefit: A prospective, controlled, multicentre cohort study.

BACKGROUND: Implantable cardioverter defibrillators (ICDs) prevent sudden cardiac death. ICD implantation decisions are currently based on reduced left ventricular ejection fraction (LVEF≤35%). However, in some patients, the non-arrhythmic death risk predominates thus diminishing ICD-therapy benefits. Based on previous observations, we tested the hypothesis that compared to the others, patients with nocturnal respiratory rate (NRR) ≥18 breaths per minute (brpm) benefit less from prophylactic ICD implantations. METHODS: This prospective cohort study was a pre-defined sub-study of EU-CERT-ICD trial conducted at 44 centers in 15 EU countries between May 12, 2014, and September 6, 2018. Patients with ischaemic or non-ischaemic cardiomyopathy were included if meeting primary prophylactic ICD implantation criteria. The primary endpoint was all-cause mortality. NRR was assessed blindly from pre-implantation 24-hour Holters. Multivariable models and propensity stratification evaluated the interaction between NRR and the ICD mortality effect. This study is registered with ClinicalTrials.gov (NCT0206419). FINDINGS: Of the 2,247 EU-CERT-ICD patients, this sub-study included 1,971 with complete records. In 1,363 patients (61.7 (12) years; 244 women) an ICD was implanted; 608 patients (63.2 (12) years; 108 women) were treated conservatively. During a median 2.5-year follow-up, 202 (14.8%) and 95 (15.6%) patients died in the ICD and control groups, respectively. NRR statistically significantly interacted with the ICD mortality effect (p = 0.0070). While the 1,316 patients with NRR<18 brpm showed a marked ICD benefit on mortality (adjusted HR 0.529 (95% CI 0.376-0.746); p = 0.0003), no treatment effect was demonstrated in 655 patients with NRR≥18 brpm (adjusted HR 0.981 (95% CI 0.669-1.438); p = 0.9202). INTERPRETATION: In the EU-CERT-ICD trial, patients with NRR≥18 brpm showed limited benefit from primary prophylactic ICD implantation. Those with NRR<18 brpm benefitted substantially. FUNDING: European Community's 7th Framework Programme FP7/2007-2013 (602299).

The Significance of Renal Function in Response to Cardiac Resynchronisation Therapy - A Piece of a Much Larger Puzzle.

BACKGROUND: Although cardiac resynchronisation therapy (CRT) is an important player in the treatment of patients with heart failure (HF), the proportion of CRT patients with no improvement in either echocardiographic or clinical parameters remains consistently high and accounts for about 30% despite meeting CRT implantation criteria. Furthermore, in patients suffering from HF, renal dysfunction accounts for as many as 30-60%. Accordingly, CRT may improve renal function inducing a systemic haemodynamic benefit leading to increased renal blood flow. OBJECTIVES: The aim of the present study was to evaluate the importance of renal function in response to resynchronisation therapy during a 12-month follow-up period. MATERIALS AND METHODS: The study consisted of 46 HF patients qualified for implantation of cardiac resynchronisation therapy defibrillator (CRT-D). A CRT responder is defined as a person without chronic HF exacerbations during observation whose physical efficiency has improved owing to the New York Heart Association (NYHA) class improvement ≥1. RESULTS: A statistically significant difference was noted between responders and non-responders regarding creatinine level at the 3rd month (p=0.04) and, particularly, at the 12th month (p=0.02) of follow-up (100±23 vs 139±78 µmol/l). Moreover, there was a remarkable difference between both study groups with regard to GFR CKD-EPI (glomerular filtration rate (GFR) assessed using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula) at the 6th (p=0.03) and 12th month (p=0.01) of follow-up. The reference values for initial creatinine concentrations (101 µmol/l) as well as GFR CKDEPI (63 ml/min/1.73m2) were empirically evaluated to predict favourable therapeutic CRT response. CONCLUSION: Predictive value of GFR CKD-EPI and creatinine concentration for a positive response to CRT was found relevant.

How to avoid unnecessary RF applications in cavo-tricuspid isthmus: common atrial flutter ablation using 8-mm-tip mini-electrode-equipped catheter.

PURPOSE: Eight-millimeter-tip ablation catheters are characterized by poor mapping resolution as they depend on electrode size and spacing. IntellaTip MiFi XP 8-mm (Boston Scientific) catheters offer high mapping resolution due to 3 mini-electrodes (ME) located at the distal tip of the catheter and are dedicated for cavo-tricuspid isthmus (CTI) radiofrequency ablation (RFA). The aim of the study was to evaluate the usefulness, effectiveness and safety of novel IntellaTip MiFi XP catheter for CTI RFA and its ability to localize anatomical structures of the heart. METHODS: The study included 10 patients referred for atrial flutter ablation. The 3D mapping system EnSite Velocity was utilized for catheter visualization. The ME signals were used for tricuspid annulus visualization, RF delivery effectiveness assessment defined as ME signal attenuation, and localization of the gaps in the ablation line. The use of ME signals for TV annulus localization resulted in a 13.9 mm (35.5 ± 4.8 mm vs 49.4 ± 7.8 mm; p < 0.01) shorter ablation line in comparison with the potential ablation line designed using standard bipol. The ablation endpoint, bidirectional block, was achieved in all 10 cases (100%) and lasted for at least 15 min after the last RF delivery. The ablation endpoint was reached after 5.1 ± 1.67 RF applications. The total RF time was 220 ± 61 s. Total procedure time was 66 ± 13.5 min, fluoroscopy time 3.92 ± 4.21 min, and total fluoroscopy dose 40.3 ± 56.5 mGy. RESULTS: In 3 out of 10 cases, there was a need of filling the gap with 1-2 additional applications after the first linear lesion set. No additional RF applications were required at the annular end of the ablation line. The indirect comparison with previously conducted studies using a standard 8-mm ablation catheter shows that the studied catheter has at least the same or even better performance. CONCLUSIONS: The use of the novel IntellaTip MiFi XP may help to avoid unnecessary RF application especially at the annular part of cavo-tricuspid isthmus and enables a purely electrophysiological approach to atrial flutter ablation, as high-resolution ME signals help to understand local electrophysiological phenomena.

Clinical effectiveness of primary prevention implantable cardioverter-defibrillators: results of the EU-CERT-ICD controlled multicentre cohort study.

AIMS: The EUropean Comparative Effectiveness Research to Assess the Use of Primary ProphylacTic Implantable Cardioverter-Defibrillators (EU-CERT-ICD), a prospective investigator-initiated, controlled cohort study, was conducted in 44 centres and 15 European countries. It aimed to assess current clinical effectiveness of primary prevention ICD therapy. METHODS AND RESULTS: We recruited 2327 patients with ischaemic cardiomyopathy (ICM) or dilated cardiomyopathy (DCM) and guideline indications for prophylactic ICD implantation. Primary endpoint was all-cause mortality. Clinical characteristics, medications, resting, and 12-lead Holter electrocardiograms (ECGs) were documented at enrolment baseline. Baseline and follow-up (FU) data from 2247 patients were analysable, 1516 patients before first ICD implantation (ICD group) and 731 patients without ICD serving as controls. Multivariable models and propensity scoring for adjustment were used to compare the two groups for mortality. During mean FU of 2.4 ± 1.1 years, 342 deaths occurred (6.3%/years annualized mortality, 5.6%/years in the ICD group vs. 9.2%/years in controls), favouring ICD treatment [unadjusted hazard ratio (HR) 0.682, 95% confidence interval (CI) 0.537-0.865, P = 0.0016]. Multivariable mortality predictors included age, left ventricular ejection fraction (LVEF), New York Heart Association class

Long-term follow-up of implantable cardioverter-defibrillators in children: Indications and outcomes.

BACKGROUND: Validation data of the use of implantable cardioverter-defibrillators (ICD) in the pediatric population is insufficient, with limited follow-up periods. OBJECTIVES: The aim of the study was to report on 17 years of experience with implantable cardioverter-defibrillator (ICD) therapy in children and young adults. MATERIAL AND METHODS: This retrospective review included patients below the age of 18 years at the time of ICD implantation between May 2000 and December 2017. For the statistical analysis, the sample was divided into groups by gender and the type of indications for ICD implantation (primary vs secondary prevention). RESULTS: The study group included 20 children (8 female, 12 male) who underwent ICD implantation for primary or secondary prevention of sudden cardiac death (SCD). The average age at the time of the initial procedure was 15.6 years (range: 3.8-17.7 years). Primary electrical disease (PED) was present in 9 patients, cardiomyopathy (CMP) in 9 and 2 others had congenital heart defects (CHDs). The median follow-up time was 6.7 years (range: 0.4-12.5 years). The outcomes of ICD therapy were analyzed. No differences between the sexes were found in terms of treatment strategy effectiveness (p > 0.05). The girls were more often treated as primary prevention (p = 0.009). After implantation, all the patients were on optimal pharmacotherapy. Alltogether there were 126 ICD interventions in 11 patients, including 23 inadequate interventions (IA) in 2 children (18.2%).Three children (15%) died due to electrical storms. In the per-procedure analysis, the overall freedom rate from ICD lead replacement was 90%, 80% and 57% at 1, 5 and 10 years of observation, respectively. CONCLUSIONS: Implantable cardioverter-defibrillator implantation indications in children are more heterogeneous in comparison to adult population. In the pediatric population undergoing ICD implantation, the treatment strategy is influenced by gender. The rate of inappropriate ICD discharges (IA) in our group of pediatric patients was low. Rigorous pharmacotherapy and individual ICD programming seemed of paramount importance. Lead malfunctions LF constituted the most prevalent complication observed.

Appropriate Shocks and Mortality in Patients With Versus Without Diabetes With Prophylactic Implantable Cardioverter Defibrillators.

OBJECTIVE: Diabetes increases the risk of all-cause mortality and sudden cardiac death (SCD). The exact mechanisms leading to sudden death in diabetes are not well known. We compared the incidence of appropriate shocks and mortality in patients with versus without diabetes with a prophylactic implantable cardioverter defibrillator (ICD) included in the retrospective EU-CERT-ICD registry. RESEARCH DESIGN AND METHODS AND RESULTS: A total of 3,535 patients from 12 European EU-CERT-ICD centers with a mean age of 63.7 ± 11.2 years (82% males) at the time of ICD implantation were included in the analysis. A total of 995 patients (28%) had a history of diabetes. All patients had an ICD implanted for primary SCD prevention. End points were appropriate shock and all-cause mortality. Mean follow-up time was 3.2 ± 2.3 years. Diabetes was associated with a lower risk of appropriate shocks (adjusted hazard ratio [HR] 0.77 [95% CI 0.62-0.96], P = 0.02). However, patients with diabetes had significantly higher mortality (adjusted HR 1.30 [95% CI 1.11-1.53], P = 0.001). CONCLUSIONS: All-cause mortality is higher in patients with diabetes than in patients without diabetes with primary prophylactic ICDs. Subsequently, patients with diabetes have a lower incidence of appropriate ICD shocks, indicating that the excess mortality might not be caused primarily by ventricular tachyarrhythmias. These findings suggest a limitation of the potential of prophylactic ICD therapy to improve survival in patients with diabetes with impaired left ventricular function.

Present criteria for prophylactic ICD implantation: Insights from the EU-CERT-ICD (Comparative Effectiveness Research to Assess the Use of Primary ProphylacTic Implantable Cardioverter Defibrillators in EUrope) project.

BACKGROUND: The clinical effectiveness of primary prevention implantable cardioverter defibrillator (ICD) therapy is under debate. It is urgently needed to better identify patients who benefit from prophylactic ICD therapy. The EUropean Comparative Effectiveness Research to Assess the Use of Primary ProphylacTic Implantable Cardioverter Defibrillators (EU-CERT-ICD) completed in 2019 will assess this issue. SUMMARY: The EU-CERT-ICD is a prospective investigator-initiated non-randomized, controlled, multicenter observational cohort study done in 44 centers across 15 European countries. A total of 2327 patients with heart failure due to ischemic heart disease or dilated cardiomyopathy indicated for primary prophylactic ICD implantation were recruited between 2014 and 2018 (>1500 patients at first ICD implantation, >750 patients non-randomized non-ICD control group). The primary endpoint was all-cause mortality, and first appropriate shock was co-primary endpoint. At baseline, all patients underwent 12­lead ECG and Holter-ECG analysis using multiple advanced methods for risk stratification as well as documentation of clinical characteristics and laboratory values. The EU-CERT-ICD data will provide much needed information on the survival benefit of preventive ICD therapy and expand on previous prospective risk stratification studies which showed very good applicability of clinical parameters and advanced risk stratifiers in order to define patient subgroups with above or below average ICD benefit. CONCLUSION: The EU-CERT-ICD study will provide new and current data about effectiveness of primary prophylactic ICD implantation. The study also aims for improved risk stratification and patient selection using clinical risk markers in general, and advanced ECG risk markers in particular.

Atrial high-rate episodes: prevalence, stroke risk, implications for management, and clinical gaps in evidence.

Self-terminating atrial arrhythmias are commonly detected on continuous rhythm monitoring, e.g. by pacemakers or defibrillators. It is unclear whether the presence of these arrhythmias has therapeutic consequences. We sought to summarize evidence on the prevalence of atrial high-rate episodes (AHREs) and their impact on risk of stroke. We performed a comprehensive, tabulated review of published literature on the prevalence of AHRE. In patients with AHRE, but without atrial fibrillation (AF), we reviewed the stroke risk and the potential risk/benefit of oral anticoagulation. Atrial high-rate episodes are found in 10-30% of AF-free patients. Presence of AHRE slightly increases stroke risk (0.8% to 1%/year) compared with patients without AHRE. Atrial high-rate episode of longer duration (e.g. those >24 h) could be associated with a higher stroke risk. Oral anticoagulation has the potential to reduce stroke risk in patients with AHRE but is associated with a rate of major bleeding of 2%/year. Oral anticoagulation is not effective in patients with heart failure or survivors of a stroke without AF. It remains unclear whether anticoagulation is effective and safe in patients with AHRE. Atrial high-rate episodes are common and confer a slight increase in stroke risk. There is true equipoise on the best way to reduce stroke risk in patients with AHRE. Two ongoing trials (NOAH-AFNET 6 and ARTESiA) will provide much-needed information on the effectiveness and safety of oral anticoagulation using non-vitamin K antagonist oral anticoagulants in patients with AHRE.

Clinical Usefulness of N-terminal Prohormone of Brain Natriuretic Peptide and High Sensitivity Troponin T in Patients with Heart Failure Undergoing Cardiac Resynchronization Therapy.

BACKGROUND: Cardiac resynchronization therapy (CRT) is a valuable intracardiac device--based treatment option for a subgroup of patients with advanced heart failure (HF) and QRS prolongation. However, still a significant proportion of patients do not benefit from CRT implantation, labeled as non-responders. OBJECTIVES: The aim of the present study was to evaluate the N-terminal prohormone of brain natriuretic peptide (NT-pro BNP) and high sensitivity troponin T (cTnThs) value as predictors of CRT response in a 12-month observation. MATERIALS AND METHODS: The study included 46 patients with HF and implanted CRT-D. Levels of NT-pro BNP and cTnThs were assessed during a 12 month follow up. RESULTS: 46 consecutive patients (76% men) with a mean age of 64±8 were observed for 12 months. The CRT response criteria was met by 26 patients (56,5%). A significant decline in the NT-pro BNP concentrations was documented in responders (p=0.001). Moreover, ΔNT-pro BNP by at least 579 pg/ml had high sensitivity and specificity for identifying the CRT responders. There were no statistically significant differences in the results of cTnThs between the two study groups. CONCLUSION: The relative change in the level of NT-pro BNP by at least 43,5% allows to identify the responders to CRT after 12 months of follow-up. Serial measurements of NT-pro BNP can be a valuable tool for monitoring the effectiveness of CRT.

A Retrospective Study of Atrial Fibrillation Following Cavotricuspid Isthmus Ablation for Atrial Flutter.

BACKGROUND Catheter radiofrequency ablation for typical atrial flutter is considered to be safe and effective. However, atrial fibrillation (AF) following cavotricuspid isthmus ablation for atrial flutter has been reported in patients without a previous history of AF, which has implications for the decision to use oral anticoagulation. This retrospective study at a single center aimed to evaluate the occurrence of AF in patients after successful cavotricuspid isthmus ablation of typical atrial flutter and to determine the incidence and associations with AF during follow-up. MATERIAL AND METHODS Between January 2011 and July 2017, of 110 consecutive patients who underwent cavotricuspid isthmus ablation for typical atrial flutter, 67 patients had no previous history of AF, of which 40 patients underwent follow-up. The 40 patients included in this retrospective clinical study included 34 men and 6 women, with a mean age of 67±10 years. RESULTS Forty patients underwent post-ablation follow-up for 46±23 months, and 12 patients (30%) developed AF; six patients (15%) experienced recurrent of atrial flutter. More than half of the patients with post-ablation AF were asymptomatic with a European Heart Rhythm Association (EHRA) score of 1, and univariate analysis showed the absence of variables associated with the prevalence of AF. CONCLUSIONS Following cavotricuspid isthmus ablation for atrial flutter, recurrence of atrial flutter was found in 15% of cases, and asymptomatic AF occurred in 30%. These findings have implications for the use of post-ablation oral anticoagulation treatment, which is often discontinued following ablation therapy and before patient follow-up.