Regional differences in outcomes with ablation versus drug therapy for atrial fibrillation: Results from the CABANA trial.

BACKGROUND: The finding of unexpected variations in treatment benefits by geographic region in international clinical trials raises complex questions about the interpretation and generalizability of trial findings. We observed such geographical variations in outcome and in the effectiveness of atrial fibrillation (AF) ablation versus drug therapy in the Catheter Ablation vs Antiarrhythmic Drug Therapy for Atrial Fibrillation (CABANA) trial. This paper describes these differences and investigates potential causes. METHODS: The examination of treatment effects by geographic region was a prespecified analysis. CABANA enrolled patients from 10 countries, with 1,285 patients at 85 North American (NA) sites and 919 at 41 non-NA sites. The primary endpoint was a composite of death, disabling stroke, serious bleeding, or cardiac arrest. Death and first atrial fibrillation recurrence were secondary endpoints. RESULTS: At least 1 primary endpoint event occurred in 157 patients (12.2%) from NA and 33 (3.6%) from non-NA sites over a median 54.9 and 40.5 months of follow-up, respectively (NA/non-NA adjusted hazard ratio (HR) 2.18, 95% confidence interval (CI) 1.48-3.21, P < .001). In NA patients, 78 events occurred in the ablation and 79 in the drug arm, (HR 0.91, 95% CI 0.66, 1.24) while 11 and 22 events occurred in non-NA patients (HR 0.51, 95% CI 0.25,1.05, interaction P = .154). Death occurred in 53 ablation and 51 drug therapy patients in the NA group (HR 0.96, 95% CI 0.65,1.42) and in 5 ablation and 16 drug therapy patients in the non-NA group (HR 0.32, 95% CI 0.12,0.86, interaction P = .044). Adjusting for baseline regional differences or prognostic risk variables did not account for the regional differences in treatment effects. Atrial fibrillation recurrence was reduced by ablation in both regions (NA: HR 0.54, 95% CI 0.46, 0.63; non-NA: HR 0.44, 95% CI 0.30, 0.64, interaction P = .322). CONCLUSIONS: In CABANA, primary outcome events occurred significantly more often in the NA group but assignment to ablation significantly reduced all-cause mortality in the non-NA group only. These differences were not explained by regional variations in procedure effectiveness, safety, or patient characteristics. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT0091150; https://clinicaltrials.gov/study/NCT00911508.

Ten years of subcutaneous defibrillator therapy: Consolidated clinical evidence and future perspectives.

The subcutaneous implantable cardioverter defibrillator (S-ICD) was developed as an alternative to the traditional transvenous implantable cardioverter defibrillator (TV-ICD), aiming to provide easier implantation, simplified detection algorithm of malignant ventricular arrhythmias and prevention from placing components in the cardiovascular system. The S-ICD is implanted subcutaneously or intramuscularly with the generator placed in the left midaxillary line and the lead tunneled subcutaneously in the left para-sternal region. Preimplant electrocardiogram screening is recommended to prevent implantation in patients at high risk of T wave over-sensing. Currently, the S-ICD is unsuitable for patients requiring pacing or cardiac resynchronization. Since the beginning, the S-ICD underwent extensive preclinical investigation until the first prospective multicentre trial demonstrating high efficacy and safety led to market release. While earlier studies focused on younger patients with higher ejection fraction, more recent studies showed favorable outcomes even in patients with comorbidities similar to those typically observed in patients receiving TV-ICD. The development of second and third generation devices has contributed to reduce inappropriate shocks and overcome previous limitations. The aim of this paper is to review the evidence in the literature over the past decade supporting S-ICD as a valid alternative to TV-ICD in terms of safety and efficacy, highlighting the improvements in technology, as well as outcomes.

Metabolic disorders affecting the liver and heart: Therapeutic efficacy of miRNA-based therapies?

Liver and heart disease are major causes of death worldwide. It is known that metabolic alteration causing type 2 diabetes (T2D) and Nonalcoholic fatty liver (NAFLD) coupled with a derangement in lipid homeostasis, may exacerbate hepatic and cardiovascular diseases. Some pharmacological treatments can mitigate organ dysfunctions but the important side effects limit their efficacy leading often to deterioration of the tissues. It needs to develop new personalized treatment approaches and recent progresses of engineered RNA molecules are becoming increasingly viable as alternative treatments. This review outlines the current use of antisense oligonucleotides (ASOs), RNA interference (RNAi) and RNA genome editing as treatment for rare metabolic disorders. However, the potential for small non-coding RNAs to serve as therapeutic agents for liver and heart diseases is yet to be fully explored. Although miRNAs are recognized as biomarkers for many diseases, they are also capable of serving as drugs for medical intervention; several clinical trials are testing miRNAs as therapeutics for type 2 diabetes, nonalcoholic fatty liver as well as cardiac diseases. Recent advances in RNA-based therapeutics may potentially facilitate a novel application of miRNAs as agents and as druggable targets. In this work, we sought to summarize the advancement and advantages of miRNA selective therapy when compared to conventional drugs. In particular, we sought to emphasise druggable miRNAs, over ASOs or other RNA therapeutics or conventional drugs. Finally, we sought to address research questions related to efficacy, side-effects, and range of use of RNA therapeutics. Additionally, we covered hurdles and examined recent advances in the use of miRNA-based RNA therapy in metabolic disorders such as diabetes, liver, and heart diseases.

Efficacy of cryoablation in atrial fibrillation: comparison with antiarrhythmic therapy.

Atrial fibrillation (AF) represents the most common arrhythmia in clinical practice, characterized by irregular atrial electrical activity originating mainly in and around the pulmonary veins. This condition can manifest itself symptomatically or silently but still dangerously. Complications associated with AF include stroke, heart failure, worst clinical outcome in patients with underlying conditions, increased emergency room visits, hospitalizations, and cardiovascular mortality. Currently, according to the main international guidelines, antiarrhythmic therapy is considered the first choice for rhythm control in patients with AF despite modest efficacy and non-negligible side effects. In recent decades, radiofrequency catheter ablation has emerged as an alternative to antiarrhythmic drugs for rhythm control. Cryoablation was developed with the aim of reducing procedural times and reducing complications related to the ablative procedure with radiofrequency without losing efficacy. Recent studies conducted with rigour and scientific solidity have demonstrated on the one hand that the results of this technique are not inferior compare with radiofrequency. This study aims to compare data on the safety and efficacy of cryoablation with those obtained from antiarrhythmic drugs through a review of the most recent scientific evidence.

A Single-lead ECG algorithm to differentiate right from left manifest accessory pathways: A reappraisal of the P-Delta interval.

INTRODUCTION: Despite numerous ECG algorithms being developed to localize the site of manifest accessory pathways (AP), they often require stepwise multiple-lead analysis with variable accuracy, limitations, and reproducibility. The study aimed to develop a single-lead ECG algorithm incorporating the P-Delta interval (PDI) as an adjunct criterion to discriminate between right and left manifest AP. METHODS: Consecutive WPW patients undergoing electrophysiological study (EPS) were retrospectively recruited and split into a derivation and validation group (1:1 ratio). Sinus rhythm ECG analysis in lead V1 was performed by three independent investigators blinded to the EPS results. Conventional ECG parameters and PDI were assessed through the global cohort. RESULTS: A total of 140 WPW patients were included (70 for each group). A score-based, single-lead ECG algorithm was developed through derivation analysis incorporating the PDI, R/S ratio, and QRS onset polarity in lead V1. The validation group analysis confirmed the proposed algorithm's high accuracy (95%), which was superior to the previous ones in predicting the AP side (p < 0.05). A score of ≤+1 was 96.5% accurate in predicting right AP while a score of ≥+2 was 92.5% accurate in predicting left AP. The new algorithm maintained optimal performance in specific subgroups of the global cohort showing an accuracy rate of 90%, 92%, and 96% in minimal pre-excitation, posteroseptal AP, and pediatric patients, respectively. CONCLUSIONS: A novel single-lead ECG algorithm incorporating the PDI interval with previous conventional criteria showed high accuracy in differentiating right from left manifest AP comprising pediatric and minimal pre-excitation subgroups in the current study.

Catheter-induced right bundle branch block: Practical implications for the cardiac electrophysiologist.

The right bundle branch (RBB), due to its endocardial course, is susceptible to traumatic block caused by "bumping" during right-heart catheterization. In the era of cardiac electrophysiology, catheter-induced RBB block (CI-RBBB) has become a common phenomenon observed during electrophysiological studies and catheter ablation procedures. While typically transient, it may persist for the entire procedure time. Compared to pre-existing RBBB, the transient nature of CI-RBBB allows for comparative analysis relative to the baseline rhythm. Furthermore, unlike functional RBBB, it occurs at similar heart rates, making the comparison of conduction intervals more reliable. While CI-RBBB can provide valuable diagnostic information in various conditions, it is often overlooked by cardiac electrophysiologists. Though it is usually a benign and self-limiting conduction defect, it may occasionally lead to diagnostic difficulties, pitfalls, or undesired consequences. Avoidance of CI-RBBB is advised in the presence of baseline complete left bundle branch block and when approaching arrhythmic substrates linked to the right His-Purkinje-System, such as fasciculo-ventricular pathways, bundle branch reentry, and right-Purkinje focal ventricular arrhythmias. This article aims to provide a comprehensive practical review of the electrophysiological phenomena related to CI-RBBB and its impact on the intrinsic conduction system and various arrhythmic substrates.

Catheter ablation of left atrial tachycardia adjacent to a septal closure device: A multifaceted challenge?

Catheter ablation (CA) of left atrial tachycardia adjacent to implanted septal closure devices represents a multifaceted challenge. We describe the case of a 57-year-old patient with remote percutaneous closure of atrial septal defect who underwent successful CA of left atrial tachycardia adjacent to the septal device using a transaortic approach and RF energy. Besides the technical difficulties and associated risks, interference between the device and applied RF parameters may limit ablation efficiency. Further research is required to evaluate the safety, efficacy, and optimal energy type/parameters when ablating arrhythmias adjacent to these devices.

How much does the presentation pattern of atrial fibrillation affect thrombo-embolic risk and mortality?

Atrial fibrillation (AF) is associated with a substantial increase in mortality and morbidity. Systemic thrombo-embolism is the most serious complication associated with this arrhythmia. The use of anticoagulant drugs is the cornerstone of therapy for the prophylaxis of stroke and peripheral ischaemia in these patients. The current guidelines recommend the use of anticoagulant drugs based on the thrombo-embolic risk profile of each individual patient calculated by SCORE based on the presence or absence of clinical risk factors and regardless of the presentation pattern of AF. A review of literature data investigating the effect of AF presentation pattern on thrombo-embolic risk and mortality showed an increased risk of both thrombo-embolic events and death in patients with non-paroxysmal AF compared to patients with paroxysmal AF. Most of these studies, however, consist of post-hoc analyses of large trials or observational studies and meta-analyses derived from these, resulting in an important limitation in the interpretation of data derived from such studies. At the same time, these data suggest the need for both new therapies to prevent AF progression and for further studies to explore the integration of AF presentation pattern into models of thrombo-embolic risk.

Air entrapment as a potential cause of early subcutaneous implantable cardioverter defibrillator malfunction: a systematic review of the literature.

AIMS: Air entrapment (AE) has been reported as a potential cause of early inappropriate shocks (ISs) following subcutaneous implantable cardioverter defibrillator (S-ICD) implantation, but a cause-effect relationship is not always evident. This systematic review aims to analyse this phenomenon concerning implantation techniques, electrogram (EGM) features, radiologic findings, and patient management. METHODS AND RESULTS: A systematic search was conducted using PubMed, Embase, and Google Scholar databases following the PRISMA guidelines to obtain all available literature data since 2010 on S-ICD malfunctions possibly due to AE. The final analysis included 54 patients with AE as a potential cause of S-ICD malfunction. Overall, the aggregate incidence of this condition was 1.2%. Of ICD malfunctions possibly due to AE, 93% were ISs, and 95% were recorded within the first week following implantation. Radiologic diagnosis of AE was confirmed in 28% of the entire study cohort and in 68% of patients in whom this diagnostic examination was reported. At the time of device malfunction, EGMs showed artefacts, baseline drift, and QRS voltage reduction in 95, 76, and 67% of episodes, respectively. Management included ICD reprogramming or testing, no action (observation), and invasive implant revision in 57, 33, and 10% of patients, respectively. No recurrences occurred during follow-up, irrespective of management performed. CONCLUSIONS: Device malfunction possibly due to AE may occur in ∼1% of S-ICD recipients. Diagnosis is strongly suggested by early occurrence, characteristic EGM features, and radiologic findings. Non-invasive management, principally device reprogramming, appears to be effective in most patients.

The many NOs to the use of Class IC antiarrhythmics: weren't the guidelines too strict?

Class IC antiarrhythmic drugs (AADs) currently represent a cornerstone in the therapy of atrial fibrillation, both for the restoration of sinus rhythm and for the prophylaxis of long-term relapses. They also play an important role in the treatment of idiopathic ventricular arrhythmias. Following the results of the Cardiac Arrhythmia Suppression Trial study, flecainide and by extension the other Class IC AADs were contraindicated in patients with ischaemic and structural heart disease, due to their pro-arrhythmic effect and the consequent increase in mortality observed in the study. Recent studies carried out on patients with chronic coronary heart disease without previous heart attacks and/or residual ischaemia have shown a good safety profile for this class of drugs. In addition, other studies have shown excellent efficacy in the absence of pro-arrhythmic effects of Class IC AADs in patients with structural heart disease such as arrhythmogenic right ventricular cardiomyopathy (ARVC) and tachy-cardiomyopathy. The purpose of this review is to evaluate the appropriate use of Class IC AADs in the different patient subgroups, in the light of the evidence and new diagnostic and therapeutic tools available.

Predictors of sinus rhythm 6 weeks after cardioversion of atrial fibrillation: a pre-planned post hoc analysis of the X-VeRT trial.

AIMS: Using a pre-planned post hoc analysis of patients included in X-VeRT, we evaluated predictors of sinus rhythm at 6 weeks after planned cardioversion. METHODS AND RESULTS: Receiver operating characteristic curves and logistic regression models were used to evaluate continuous and categorical variables as predictors of sinus rhythm 6 at weeks from cardioversion (end of study). The primary analysis was performed in successfully cardioverted patients with an evaluable electrocardiogram at end of study. A second analysis evaluated additional patients who spontaneously restored sinus rhythm before planned cardioversion. Of the 1504 patients with atrial fibrillation of >48 h or of unknown duration who were randomly assigned to either rivaroxaban or vitamin K antagonist, 1039 (64.6 ± 10.3 years, 73.4% male) underwent planned cardioversion and were included in this study. Patients receiving early cardioversion (i.e. between 1 and 5 days from hospitalization) had a 67% higher probability to have sinus rhythm at end of study than those who received delayed cardioversion (i.e. between 21 and 56 days from hospitalization) [odds ratio (OR) 1.67, confidence interval (CI) 1.27-2.18; P < 0.0001]. In a multivariate analysis of 17 baseline variables, patients with a CHADS2 score of 0 were 33% less likely to be in sinus rhythm than those with a CHADS2 score ≥2 (OR 0.66, CI 0.47-0.94; P = 0.0225). In the secondary analysis, spontaneous restoration of sinus rhythm was also found to predict sinus rhythm at end of study (OR 8.62, CI 1.54-48.16; P = 0.0142). CONCLUSION: In X-VeRT, early cardioversion and high CHADS2 scores predicted sinus rhythm at 6 weeks from cardioversion.

Periprocedural anticoagulation in the uninterrupted edoxaban vs. vitamin K antagonists for ablation of atrial fibrillation (ELIMINATE-AF) trial.

AIMS: This post hoc analysis of ELIMINATE-AF evaluated requirements of unfractionated heparin (UFH) and procedure-related bleeding in atrial fibrillation (AF) patients undergoing ablation with uninterrupted edoxaban or vitamin K antagonist (VKA) therapy. METHODS AND RESULTS: Patients were randomized 2:1 to once-daily edoxaban 60 mg (or dose-reduced 30 mg) or dose-adjusted VKA (target international normalized ratio: 2.0-3.0). Uninterrupted anticoagulation was mandated for 21-28 days' pre-ablation and 90 days' post-ablation. During ablation, UFH administration targeted an activated clotting time (ACT) of 300-400 s. Periprocedural bleeding was differentiated between procedure-related (bleeding at puncture side, cardiac tamponade) and unrelated events. Of 614 randomized patients, 553 received study drug and underwent catheter ablation (edoxaban n = 375; VKA n = 178). The median (Q1-Q3) time from last dose to ablation procedure was 14.8 (13.3-16.5) vs. 16.5 (14.8-19.5) h (edoxaban vs. VKA group, respectively). Mean ACT (SD) ≥300 s was observed in 52% edoxaban- vs. 76% VKA-treated patients, despite a higher mean (SD) UFH dose in the edoxaban vs. VKA group [14 261 (6397) IU vs. 11 473 (4300) IU; exploratory P-value < 0.0001]. In the edoxaban group, 13 patients (3.5%) had procedure-related bleeds of whom 9 had received an UFH dose above the median (13 000 IU). In the VKA arm, 7 patients (3.9%) had procedure-related bleeds of whom 3 had received an UFH dose above the median (10 225 IU). CONCLUSION: The rate of procedure-related major/clinically relevant non-major bleeding did not differ between the treatment arms despite higher doses of UFH used with edoxaban vs. VKA to achieve a target ACT during AF ablation.

How effective is cryoablation in the treatment of atrial fibrillation?

Pulmonary vein isolation is the standard for atrial fibrillation ablation. Although the most commonly applied energy source is radiofrequency (RF), cryoablation has rapidly evolved as a powerful one-shot tool, particularly after the introduction of the second-generation catheter, gaining widespread use in recent years. The efficacy in maintaining sinus rhythm after a first ablative procedure is ∼70-80%, and the randomization studies comparing cryoablation to RF have not been able to reveal significant differences up to now. Although different baseline characteristics may influence the efficacy of cryoablation, we are not yet able to distinguish which patients may benefit from a personalized choice of ablative source. Regarding safety, cryoballoon ablation appears to be associated with a lower rate of pericardial effusion and cardiac tamponade, mainly due to the lack of risk of overheating. The other side of the coin is a higher incidence of phrenic nerve damage, which occurs in 1-2% of procedures. In conclusion, we do not yet have definitive data to affirm the superiority of the RF technique over that of cryoablation. The choice of energy source currently depends on the availability of the centre and on the experience of the operator.

Stroke and mortality risk after atrial fibrillation ablation: lesson from the CABANA trial.

The CABANA trial is a randomized controlled study comparing catheter ablation vs. conventional medical therapy in atrial fibrillation (AF) patients. The results of the study showed that catheter ablation did not have a significant reduction of strokes, deaths, serious bleeding, or cardiac arrest compared to medical therapy. However, a significant improvement in AF recurrences, quality of life, and symptom relief has been shown after catheter ablation compared to drug therapy. The mixed results of the study emphasized an active controversy in the cardiology community on the interpretation of the data and their use in current clinical practice. In this review, we summarized the principal controversy points of the trial describing the strengths and weaknesses of the study design and analysis.

Atrial fibrillation ablation in heart failure.

Atrial fibrillation (AF) and heart failure (HF) commonly coexist in the same patient and either condition predisposes to the other. Several mechanisms promote the pathophysiological relationship between AF and HF, reducing quality of life, increasing the risk of stroke, and worsening HF progression. Although restoration and maintenance of sinus rhythm would be ideal for those patients, several trials comparing rhythm and rate control failed to show a benefit of rhythm control strategy, achieved with pharmacological therapy, in terms of hospitalization for HF or death. Catheter ablation is a well-established option for symptomatic AF patients, resistant to drug therapy, with normal cardiac function. Several recent studies have shown an improvement in clinical outcomes after AF ablation in HF patients highlighting the emerging role of the invasive approach in this subset of patients. However, several concerns regarding patients' selection and standardization of the procedure still remain to be addressed.

Uninterrupted edoxaban vs. vitamin K antagonists for ablation of atrial fibrillation: the ELIMINATE-AF trial.

AIMS: Edoxaban is a direct factor Xa inhibitor approved for stroke prevention in atrial fibrillation (AF). Uninterrupted edoxaban therapy in patients undergoing AF ablation has not been tested. METHODS AND RESULTS: The ELIMINATE-AF trial, a multinational, multicentre, randomized, open-label, parallel-group study, was conducted to assess the safety and efficacy of once-daily edoxaban 60 mg (30 mg in patients indicated for dose reduction) vs. vitamin K antagonists (VKAs) in AF patients undergoing catheter ablation. Patients were randomized 2:1 to edoxaban vs. VKA. The primary endpoint (per-protocol population) was time to first occurrence of all-cause death, stroke, or International Society of Thrombosis and Haemostasis-defined major bleeding during the period from the end of the ablation procedure to end of treatment (90 days). Overall, 632 patients were enrolled, 614 randomized, and 553 received study drug and underwent ablation; 177 subjects underwent brain magnetic resonance imaging to assess silent cerebral infarcts. The primary endpoint (only major bleeds occurred) was observed in 0.3% (1 patient) on edoxaban and 2.0% (2 patients) on VKA [hazard ratio (95% confidence interval): 0.16 (0.02-1.73)]. In the ablation population (modified intent-to-treat population including patients with ablation), the primary endpoint was observed in 2.7% of edoxaban (N = 10) and 1.7% of VKA patients (N = 3) between start of ablation and end of treatment. There were one ischaemic and one haemorrhagic stroke, both in patients on edoxaban. Cerebral microemboli were detected in 13.8% (16) patients who received edoxaban and 9.6% (5) patients in the VKA group (nominal P = 0.62). CONCLUSION: Uninterrupted edoxaban therapy represents an alternative to uninterrupted VKA treatment in patients undergoing AF ablation.

[Recommendations for the management of COVID 19 patients regarding proarrhythmic effects of some current treatments, specifically if these patients suffer from arrhythmias, and for those receiving antiarrhythmic therapy.]

Recommendation provides information to employees of medical departments at any level and primarily primary care about the possible proarrhythmic and adverse effects of drugs used for the treatment of COVID-19 patients and the features of therapy for COVID-19 patients with heart rhythm and conduction disorders receiving permanent antiarrhythmic therapy.

[Recommendations of the Eurasian Arrhythmology Association (EURA) for the diagnosis and treatment of patients with arrhythmias and conduction disorders during the COVID-19 pandemic].

The beginning of 2020 was characterized by the development of a new coronavirus pandemic (COVID-19). Information about the epidemiology, etiology, pathogenesis, clinical and laboratory diagnostics, as well as prevention and therapy for this disease is constantly being expanded and reviewed. The COVID-19 pandemic creates the need for the emergence of new conditions of specialized care for patients with heart rhythm and conduction disorders [1]. These recommendations are intended for general practitioners, internists, cardiologists, electrophysiologists/arrhythmologists, cardiovascular surgeons, functional diagnostics doctors, anesthesiologists-resuscitators, laboratory diagnostics specialists, health care organizers in the system of organizations and healthcare institutions that provide specialized care to patients with heart rhythm and conduction disorders.