Antiarrhythmic Drug Therapy for Acute Management of Atrial Fibrillation and Atrial Flutter.

Relation of the Severity of Obstructive Sleep Apnea in Response to Anti-Arrhythmic Drugs in Patients With Atrial Fibrillation or Atrial Flutter

POSTER PRESENTATIONS

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Introduction: Atrial fibrillation is the most common cardiac arrhythmia and is an independent risk factor for mortality across a wide age range in both men and women. Management methods of atrial fibrillation have been thoroughly investigated through numerous trials exploring various treatment modalities. There has been a preference for rate control as the initial approach, but recent studies, particularly the EAST-AFNET 4 trial, point out several clinical settings in which rhythm control is preferable. To evaluate new paradigms in the acute management of atrial fibrillation, our meta-analysis provides a current, curated examination of the major landmark trials in the management of atrial fibrillation along with the most recent randomized controlled trials that have been published since 2022. Methods: A literature search was performed on May 2022 using PubMed and OVID Medline databases for study identification. Combinations of the search terms atrial fibrillation, rate control, adrenergic beta antagonists, rhythm control, anti-arrhythmia drugs, and catheter ablation were combined to conduct the literature search. Boolean operators AND and OR were used to combine terms. Results: There were no significant differences in the effects of rate and rhythm control on any outcome: all-cause mortality (RR: 0.996; CI: 0.674-1.376), cardiovascular mortality (RR: 0.957; CI: 0.601-1.413), arrhythmic/sudden death mortality (RR: 0.954; CI: 0.445-1.816), stroke/transient ischemic attack (RR: 1.011; CI: 0.535-1.78), and systemic embolism (RR: 1.275; CI: 0.541-2.625). Conclusions: Updated data pooled from randomized control trials in patients with atrial fibrillation suggests that rhythm and rate control strategies have no statistically significant differences on major clinical outcomes. Additional studies will be required to investigate factors favorable for rhythm-control strategies and to determine contemporary best clinical practices.

This clinical review is intended to assist emergency physicians manage patients who present to the emergency department (ED) with acute/recent-onset atrial fibrillation (AF) or flutter (AFL). This article is based primarily on the 2021 Canadian Association of Emergency Physicians (CAEP) Acute Atrial Fibrillation/Flutter Best Practices Checklist. We encourage readers to download the open access CAEP Checklist article (https://link.springer.com/article/10.1007/s43678-021-00167-y) and the free smartphone app (CAEP Atrial Fibrillation Guide). We focus on four key elements of ED care: assessment and risk stratification, rate and rhythm control, short-term and long-term stroke prevention, and disposition and follow-up. It is important to determine if AF/AFL with rapid ventricular response is a primary arrhythmia or secondary to medical causes. While it is unusual for patients with primary AF to be unstable, urgent cardioversion is occasionally required. The criteria for when cardioversion is safe have recently changed and it is essential that physicians are well versed in them. When rhythm control is not safe, provide effective and safe IV rate control. When rhythm control is safe, either pharmacological or electrical cardioversion acceptable, per patient and physician preference. Rapid ventricular pre-excitation (Wolff-Parkinson-White Syndrome) usually, but not always, requires urgent electrical cardioversion. ED physicians should prescribe oral anticoagulants at discharge if indicated. No specific direct oral anticoagulant is preferred, and references should be freely consulted for optimal dosing. Hospital admission is rarely required for acute AF/AFL patients, who should be given good discharge instructions.

While the predominant symptom(s) related to atrial fibrillation (AF) are due to either a poorly controlled—or irregular— ventricular rate, still there is some debate with regard to the optimal strategy (that is, rate or rhythm control) to treat individual patients. Indeed, recent large, randomized, controlled trials have shown that neither rate nor rhythm control was superior in reducing mortality in AF patients, although achieving rhythm control appears to improve functional class, 1 at least in the short term. Interestingly, a post hoc analysis from the AFFIRM trial found that sinus rhythm (and warfarin use) was related to improved survival but this was offset by a greater mortality from antiarrhythmic drugs (AADs). 2 Anderson et al., 3 from a large retrospective (n ¼ 40 823) Swedish nationwide study (conducted between 1995 and 2004), reported that AAD therapy was not associated with an increased mortality in AF patients. As expected, various AADs (mainly flecainide, propafenone, sotalol, and amiodarone) were used in the treatment of AF, but in this unselected, non-randomized cohort, considerably more patients were on sotalol (16%) when compared with the rest of the AADs (flecainide 2.4%, propafenone 2.6%, or amiodarone 7.3%). However, in patients with previous myocardial infarction (MI) or ischaemic heart disease, the preferred choice of AAD was amiodarone (24.3%) compared with sotalol (15%) or class-Ic drugs (8.6%). Similarly, more patients with heart failure were on amiodarone (21.5%) when compared with other AADs (sotalol 9.5%, class-Ic drugs 6.1%). The authors quoted annual mortality rates (per year/100 patient-years) of 7.4 vs. 5.3% vs. 4.3% vs. 2.5% with amiodarone, sotalol, propafenone and flecainide, respectively. Approximately a third of these unselected patients were noted to be on digoxin, whilst a fifth were on betablockers or calcium blockers—on top of prescribed AAD therapy for AF. In a Cox-regression analysis, treatment with AAD was generally associated with a lower mortality (flecainide HR 0.38, 95% CI 0.32‐0.44; propafenone HR 0.65, 95% CI 0.58‐0.71; sotalol HR 0.65, 95% CI 0.63‐0.67) but the effect of amiodarone was borderline (HR 0.94, 95% CI 0.89‐1.00). Perhaps AADs may be safe in AF after all? The quoted mortality in the paper by Anderson et l. 3 with individual AADs may well be related to disease progression rather than effect of antiarrhythmic therapy per se, and cause(s) of death in these patients is not that clear. But also, the choice of AADs were carefully selected in individual patients which also might account for the observed low mortality. These observations are contrary to the post hoc analysis of AFFIRM trial data 2,4 that there was a non-significant trend towards a higher mortality in patients assigned to rhythm when compared with rate control, predominantly due to noncardiovascular causes. The significant predictors of higher noncardiovascular mortality on multivariate analysis were rhythm control, male gender, heart failure, age, and coronary artery disease. Nevertheless, this increased mortality seen in rhythm control group may well be related to adverse effects of the various AADs used (amiodarone, sotalol, disopyramide, flecainide, moricizine, procainamide, propafenone, and quinidine) in these AF patients without heart failure, although the precise mechanism(s) was not well elucidated. In a subsequent analysis using time-dependent variables towards in these patients, there was a 1.5-fold increased risk of death noted with AAD therapy after adjusting to co-variables in the presence of sinus rhythm (HR 1.49, 99% CI 1.11‐2.01). 4 The use of digoxin for rate control also appears to increase the risk of death (HR 1.42, 99% CI 1.18‐1.89) in these patients with persistent AF. 2,4 Notably, neither beta-blockers nor calcium-channel blockers had any effect on improving survival of these AF patients. Broadly similar results were noted in the Stroke Prevention in Atrial Fibrillation (SPAF) 5 trial, where there was a 2.5-fold increase in cardiac mortality (HR 2.5, 95%CI 1.3‐4.9) and a 2.6-fold increase in arrhythmic deaths (HR 2.6, 95% CI 1.2‐5.6) in AF patients on AAD therapy, even after adjusting for cardiovascular risk factors. However, AF patients with history of congestive heart failure

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Atrial fibrillation (AF) is common and highly variable in its clinical presentation and evolution. Iit causes substantial morbidity and mortality, including impaired quality of life, heart failure, systemic emboli, and stroke. An accurate diagnosis is important and should be distinguished from atrial flutter or other arrhythmias which involves the atrium. Management of patients with AF involves 3 objectives: rate control, rhythm control, and prevention of thromboembolism. A rate control strategy alone, without attempts at restoration or maintenance of sinus rhythm (SR), is reasonable in some patients with AF, especially those who are asymptomatic. In some circumstances, when the cause of AF is reversible, such as when AF occurs after cardiac surgery, no long-term therapy may be necessary. The CHADS2 scoring system can be used to risk stratify patients with nonvalvular AF to determine the need for warfarin. The risk of thromboembolism or stroke does not differ between pharmacological and electrical CV. Ablation of the AV conduction system and permanent pacing is an option for patients with rapid ventricular rates despite maximum medical therapy. However, there is growing concern about the negative effects of long-term RV pacing. Biventricular pacing may overcome many of the adverse hemodynamic effects associated with RV pacing. Pharmacological therapy to maintain SR should be considered in patients who have troublesome symptoms. Drugs should be used to decrease the frequency and duration of episodes, and to improve symptoms. AF recurrence while taking an antiarrhythmic drug is not indicative of treatment failure and does not necessitate a change in antiarrhythmic therapy. Antiarrhythmic drug choice is based on side effect profiles and the presence or absence of structural heart disease, heart failure, and hypertension. Catheter ablation for AF is currently considered a second-line therapy in highly symptomatic patients in whom one or more antiarrhythmic agents have failed. (J Karadiol Indones. 2010;31:187-95) Keywords: Atrial fibrillation, rate control, rhythm control, thromboembolisme, stroke, anticoagulation

This document is a compilation of the current American College of Cardiology Foundation/American Heart Association (ACCF/AHA) practice guideline recommendations for atrial fibrillation (AF) from the “ACC/AHA/ESC 2006 Guidelines for the Management of Patients With Atrial Fibrillation),”* the “2011 ACCF/AHA/HRS Focused Update on the Management of Patients With Atrial Fibrillation (Updating the 2006 Guideline)”† and the “2011 ACCF/AHA/HRS Focused Update on the Management of Patients With Atrial Fibrillation (Update on Dabigatran).”‡ Updated and new recommendations from 2011 are noted and outdated recommendations have been removed. No new evidence was reviewed, and no recommendations included herein are original to this document. The ACCF/AHA Task Force on Practice Guidelines chooses to republish the recommendations in this format to provide the complete set of practice guideline recommendations in a single resource. ### 1.1. Pharmacological and Nonpharmacological Therapeutic Options #### 1.1.1. Rate Control During AF Class I 1. Measurement of the heart rate at rest and control of the rate using …

Sex differences have the potential to impact diagnostic and therapeutic interventions in a wide variety of medical conditions, and cardiac arrhythmias are no exception.1 Studies evaluating pathophysiology, disease course, and therapeutic options for cardiac arrhythmias have been performed predominantly in male patients. However, catheter and device-based therapies coupled with landmark clinical trials have contributed to an improved understanding of this important aspect. The objective of this review is to present the current state of knowledge on sex differences in cardiac arrhythmias with a focus on clinical management, while highlighting gaps in knowledge that would benefit from future investigation. ### Atrial Fibrillation and Atrial Flutter #### Disease Burden Atrial fibrillation (AF) and atrial flutter (AFL) are the most commonly encountered tachyarrhythmias in clinical practice, with significant implications for public health and healthcare costs. Stroke, hospitalization, and loss of productivity are the major consequences of AF.2 The incidence of AF (per 1000 person-years) is reported to be between 1.6 and 2.7 in women and between 3.8 and 4.7 in men.2 The age-adjusted incidence and prevalence of AF is lower in women compared with that in men, and accordingly, the lifetime risk of AF from the Framingham Heart Study at 40 years of age was higher in men (26.0% for men versus 23.0% for women).3 Another analysis from the Framingham Heart Study demonstrated no significant sex differences in the risk of developing AFL.4 The prevalence of AF continues to rise among both men and women. In a study investigating the global burden of disease from 1980 to 2010, there was not only an increase in overall burden, incidence, and prevalence of AF, but most importantly an increase in AF-associated mortality in both men and women (Figure 1).5 The age-adjusted mortality for women was consistently higher compared with that for men from 1990 to 2010 (Figure …

Variation in Management of Recent-Onset Atrial Fibrillation and Flutter Among Academic Hospital Emergency Departments

Information about a real patient is presented in stages (boldface type) to an expert clinician (Dr Valentin Fuster), who responds to the information, sharing his reasoning with the reader (regular type). A discussion by the authors follows. A 61-year-old man presents with 2 weeks of exertional dyspnea. Pertinent medical history includes hypertension, nephrolithiasis, and internal hemorrhoids. He takes no medications and has no known drug allergies. His father died after a myocardial infarction at 57 years of age. He formerly smoked 1 pack of cigarettes daily for 15 years but ceased tobacco use 10 years before presentation. He ingests 2 glasses of alcohol weekly and denies illicit drug use. His caffeine intake is limited. He is an architect and is married, with healthy children. On physical examination, his temperature is 98.0°F, blood pressure is 130/85 mm Hg bilaterally, pulse is irregular at 130 beats per minute, and respiratory rate is 18 breaths per minute with an oxygen saturation of 97% while breathing room air. He is a slender white man in no distress. His jugular venous pressure is elevated at 14 cm H 2 O. There is no thyromegaly, and the carotid upstrokes are brisk, without bruits. Cardiovascular examination reveals a rapid and irregular heart rhythm with variation in the intensity of the first heart sound. The point of maximal impulse is not displaced. The remainder of the chest and abdominal examination is within normal limits. The extremities are warm and show mild pitting edema. Laboratory testing is significant for normal renal function and electrolytes, but a hemogram reveals a mild thrombocytopenia of 90 000 platelets/μL. ECG demonstrates atrial fibrillation (AF) with an average ventricular rate of 123 bpm ( Figure 1 ). Figure 1. The 12-lead ECG showing atrial fibrillation with a rapid ventricular rate. Dr Valentin Fuster : This is a …

Background. Sepsis is often accompanied by arrhythmias and conduction disorders. It can be assumed that pacemaker cells of the sinoatrial node, strongly sensitized by massive stimulation with β1-adrenergic catecholamines, tend to trigger arrhythmias. The importance of the inflammatory component in the development of new atrial fibrillation (AF) events is also confirmed by the existence of a strong correlation between increased levels of C-reactive protein, interleukin-6 and tumor necrosis factor and the onset of fibrillation. Under the conditions of the new-onset AF, the hospital mortality of patients of general profile in the intensive care unit (ICU) significantly exceeds that for people without AF.
 Objective. To describe the features of treatment of life-threatening arrhythmias.
 Materials and methods. Analysis of literature data on this issue.
 Results and discussion. Amiodarone, diltiazem and lidocaine are the most commonly used treatments for life-threatening arrhythmias. According to a UK-wide study, amiodarone is used to treat new-onset AF in ICU in 80.94 % of cases, β-blockers (BB) – in 11.60 %, other antiarrhythmic drugs (AAD) – in 3.87 %, and digoxin – in 3.31 %. However, this tactic is not in line with the existing guidelines. According to the recommendations for the heart rate (HR) control in emergency care for AF (Bokeria L.A. et al., 2017), in an acute situation in the absence of ventricular pre-excitation syndrome intravenous administration of BB or non-dihydropyridine calcium channel blockers (CCB) is recommended to slow ventricular rhythm in patients with AF. Caution should be taken in patients with hypotension or heart failure. For the last group of patients intravenous administration of cardiac glycosides or amiodarone is recommended. In patients with ventricular pre-excitation syndrome, class I AAD or amiodarone are the drugs of choice. In presence of the pre-excitation syndrome and AF BB, non-dihydropyridine CCB, digoxin and adenosine are contraindicated. The guidelines for the management of AF patients, developed in 2017 by the European Society of Cardiology in collaboration with the European Association of Cardiothoracic Surgery, recommend to use different management tactics depending on the left ventricular ejection fraction (LV EF). In case of LV EF <40 % or signs of heart failure, the lowest effective dose of BB should be prescribed to achieve rhythm control. Amiodarone is prescribed to hemodynamically unstable patients or to individuals with severely reduced LV EF. The primary goal of treatment is to achieve a HR <110 beats/min. In the absence of this result, digoxin should be added. In case of LV EF ≥40 %, BB, or diltiazem, or verapamil should be administered. In the absence of clinical result, digoxin should be added. Practical models of AF treatment in sepsis have demonstrated the superiority of BB over CCB, digoxin and amiodarone (Walkey A.J. et al., 2016). BB weaken the stimulating effect of the sympathetic part of the autonomic nervous system on the myocardium, have a negative chronotropic effect, improve the contractility of ischemized cardiomyocytes, slow atrioventricular conduction, reduce myocardial oxygen demand, and apoptosis. Esmolol (Biblok, “Yuria-Pharm”) is indicated for supraventricular tachycardia (except for ventricular pre-excitation syndrome) and for the rapid control of ventricular rhythm in patients with AF or atrial flutter in the pre- and postoperative periods or in other circumstances when it is necessary to normalize ventricular rhythm with a short-acting drug. Studies show that esmolol inhibits inflammation in sepsis by increasing the expression of the antimicrobial peptide cathelicidin. Kaplan – Mayer analysis shows better survival for experimental animals with sepsis receiving esmolol compared to animals in the 0.9 % NaCl group (Ibrahim-Zada I. et al., 2014).
 Conclusions. 1. Sepsis is often accompanied by arrhythmias and conduction disorders. 2. Under the conditions of new-onset AF, the hospital mortality of patients of general somatic profile in ICU significantly exceeds the number for people without AF. 3. In case of AF and LV EF <40 % or signs of heart failure, the lowest effective dose of BB should be prescribed to achieve rhythm control. 4. In case of LV EF ≥40 %, BB, or diltiazem, or verapamil should be administered. 5. Esmolol is indicated for supraventricular tachycardia and for the rapid control of ventricular rhythm in patients with AF or atrial flutter. 6. Esmolol inhibits inflammation in sepsis by increasing the expression of the antimicrobial peptide cathelicidin.

Atrial fibrillation (AF) is the most common sustained arrhythmia worldwide that affects approximately one in four adults over the age of 40, leading to impaired quality of life and complications that include heart failure, stroke, and increased mortality [1]. Management strategies include stroke prevention, rate control, and rhythm control. This study by Zghaib et al. [2] included 24 990 patients with a new diagnosis of AF between 2018 and 2023 who were retrospectively included via the TriNetX database. Initial treatment lines were initiated within 4 weeks of diagnosis as either rate-control, rhythm-control, or neither. Following 4-weeks, alternative therapy lines could be initiated during patient follow-ups. This study answers an important question on how “real life” treatment is determined for newly diagnosed AF rather than presumptions of following guidelines. In this observational study, by the end of follow-up, 17 860 of the 24 990 patients at this tertiary care center were treated with either rate control only (9760 patients) or neither rate nor rhythm control (8100 patients). The other 7130 patients (29% of the total population studied) underwent rhythm control by the end of the follow-up period; 4610 patients received antiarrhythmic drug therapy only, and 2530 patients underwent an ablation procedure with or without antiarrhythmic drug therapy. When assessing patients who received any treatment, whether rate or rhythm control, these patients were younger and had a higher burden of pre-existing comorbidities such as heart failure, ischemic heart disease, and hypertension but not prior strokes. When looking at rhythm control as the therapy received, these patients were also younger but had fewer comorbidities. The authors of this study showed that in “real-life” practice, most patients received only rate control or neither rate nor rhythm control with incident AF. From the entire patient population, 71% received rate control or neither rate nor rhythm control, while 29% underwent rhythm control with either antiarrhythmic drugs or catheter ablation by the end of follow-up. This study brings forth a need to streamline patients to AF programs quickly following new diagnosis to promote earlier initiation of AF therapy, including early rhythm control. In the 2000s and 2010s, treatment for AF evolved drastically with the adoption of catheter ablation as a second line, and thereafter, in appropriate candidates as a guideline-based first-line treatment strategy. Earlier studies such as AFFIRM and RACE demonstrated noninferiority of rate control to rhythm control, while CABANA failed to show a significant reduction in death, stroke, or cardiac arrest with catheter ablation compared to antiarrhythmic drug therapy [3-5]. However, as procedural options for AF improved, including a shift towards earlier treatment, the role of rate and rhythm control evolved in parallel. In 2020, EAST-AFNET 4 showed that in patients with a new diagnosis of AF, early rhythm control was associated with reduced hospitalizations, stroke, heart failure, and cardiovascular mortality [6]. Early intervention for AF prevents cardiac remodeling, improving overall clinical outcomes and disease progression [7]. Treatment paradigms have accordingly shifted to recognize maintenance of sinus rhythm as a disease-modifying therapy in AF. There are several limitations to this study by Zghaib et al. One is that patients were studied before the 2020 EAST-AFNET 4 trial, which may limit the generalizability of the study relative to current practice. Additionally, in this database and retrospective analysis, symptom burden could not be obtained for patients, meaning symptoms' impact on referral status was not assessed. Finally, as patients were followed for a varying duration of 6 months to 6 years from AF diagnosis, the study may underrepresent patients who went on to have rhythm control after the completion of the follow-up period. The authors should be commended for this large study of “real-life” physician management of new AF diagnosis. Future studies are needed to determine how management has changed in the era of early rhythm control, and the extent to which specialized care pathways targeting earlier treatment of AF can ameliorate outcomes, cost, and be scaled broadly across practice settings.

Cryoablation may be superior to drug therapy for initial management of AFib