ABSTRACT
Heart failure (HF) with reduced ejection fraction (HFrEF) is a risk factor for drug-induced QT interval prolongation. It is unknown if HF with preserved ejection fraction (HFpEF) is also associated with an increased risk. Dofetilide and sotalol are potent QT interval-prolonging agents that are frequently used in patients with HFpEF, in whom atrial fibrillation is a common comorbidity. We tested the hypothesis that the risk of QT interval prolongation associated with dofetilide and sotalol is increased in patients with HFpEF. We conducted a retrospective cohort study conducted using electronic health records from the Indiana Network for Patient Care (January 31, 2010 -May 3, 2021). After removing patients with overlapping diagnoses of HFpEF and HFrEF, no diagnosis code, and absence of QT interval records, we identified patients taking dofetilide or sotalol among three groups: HFrEF (n = 138), HFpEF (n = 109), and no HF (n = 729). QT prolongation was defined as heart rate-corrected QT (QTc) > 500 ms during dofetilide/sotalol therapy. Unadjusted odds ratios (OR) for QT prolongation were determined by univariate analysis. Adjusted ORs were determined by generalized estimating equations (GEE) with logit link to account for an individual cluster with different times of hospitalization and covariates. QTc prolongation associated with dofetilide or sotalol occurred in 53.2%, 71.7% and 30.0% of patients with HFpEF, HFrEF, and patients with no HF, respectively. After adjusting for age, sex, race, serum potassium and magnesium concentrations, kidney function, concomitant drug therapy, and comorbid conditions, the adjusted odds of QTc prolongation were significantly higher in patients with HFpEF [OR = 1.98 (95% CI 1.17-3.33)], and in those with HFrEF [OR = 5.23, (3.15-8.67)], compared to those with no evidence of HF. The odds of QT prolongation among inpatients receiving dofetilide or sotalol were increased in patients with HFpEF and HFrEF compared to those who did not have HF.
Subject(s)
Heart Failure , Long QT Syndrome , Phenethylamines , Sotalol , Stroke Volume , Sulfonamides , Humans , Heart Failure/physiopathology , Heart Failure/drug therapy , Female , Male , Aged , Phenethylamines/adverse effects , Sotalol/adverse effects , Stroke Volume/drug effects , Retrospective Studies , Sulfonamides/adverse effects , Long QT Syndrome/chemically induced , Long QT Syndrome/physiopathology , Long QT Syndrome/epidemiology , Middle Aged , Aged, 80 and over , Electrocardiography , Anti-Arrhythmia Agents/adverse effects , Risk FactorsABSTRACT
A four-year-old Labrador Retriever was presented for intermittent tachycardia. The electrocardiogram showed sinus rhythm conducted with ventricular pre-excitation and short runs of orthodromic atrioventricular reciprocating tachycardia. Four months later, the rhythm degenerated into a symptomatic sustained tachycardia, suspected to be pre-excited atrial fibrillation, a potentially life-threatening rhythm in the presence of an accessory pathway with a short refractory period. Two days after initiating oral diltiazem, the dog deteriorated and represented with sustained orthodromic atrioventricular reciprocating tachycardia, which was terminated by a precordial chest thump. It proceeded to sinus rhythm with ventricular pre-excitation followed by an episode of pre-excited focal atrial tachycardia. A bolus of lidocaine IV successfully restored sinus rhythm and sotalol treatment was started. The dog clinically recovered but died spontaneously 24 h later. This is the first case report that describes spontaneous pre-excited focal atrial tachycardia.
Subject(s)
Anti-Arrhythmia Agents , Dog Diseases , Electrocardiography , Tachycardia, Supraventricular , Dogs , Animals , Dog Diseases/drug therapy , Tachycardia, Supraventricular/veterinary , Tachycardia, Supraventricular/drug therapy , Electrocardiography/veterinary , Anti-Arrhythmia Agents/therapeutic use , Male , Sotalol/therapeutic use , Fatal Outcome , Lidocaine/therapeutic useABSTRACT
BACKGROUND: Drug-induced QT prolongation (diLQT) is a feared side effect that could expose susceptible individuals to fatal arrhythmias. The occurrence of diLQT is primarily attributed to unintended drug interactions with cardiac ion channels, notably the hERG (human ether-a-go-go-related gene) channels that generate the delayed-rectifier potassium current (IKr) and thereby regulate the late repolarization phase. There is an important interindividual susceptibility to develop diLQT, which is of unknown origin but can be reproduced in patient-specific induced pluripotent stem cell-derived cardiomyocytes (iPS-CMs). We aimed to investigate the dynamics of hERG channels in response to sotalol and to identify regulators of the susceptibility to developing diLQT. METHODS: We measured electrophysiological activity and cellular distribution of hERG channels after hERG blocker treatment in iPS-CMs derived from patients with highest sensitivity (HS) or lowest sensitivity (LS) to sotalol administration in vivo (ie, on the basis of the measure of the maximal change in QT interval 3 hours after administration). Specific small interfering RNAs and CAVIN1-T2A-GFP adenovirus were used to manipulate CAVIN1 expression. RESULTS: Whereas HS and LS iPS-CMs showed similar electrophysiological characteristics at baseline, the late repolarization phase was prolonged and IKr significantly decreased after exposure of HS iPS-CMs to low sotalol concentrations. IKr reduction was caused by a rapid translocation of hERG channel from the membrane to the cytoskeleton-associated fractions upon sotalol application. CAVIN1, essential for caveolae biogenesis, was 2× more highly expressed in HS iPS-CMs, and its knockdown by small interfering RNA reduced their sensitivity to sotalol. CAVIN1 overexpression in LS iPS-CMs using adenovirus showed reciprocal effects. We found that treatment with sotalol promoted translocation of the hERG channel from the plasma membrane to the cytoskeleton fractions in a process dependent on CAVIN1 (caveolae associated protein 1) expression. CAVIN1 silencing reduced the number of caveolae at the membrane and abrogated the translocation of hERG channel in sotalol-treated HS iPS-CMs. CAVIN1 also controlled cardiomyocyte responses to other hERG blockers, such as E4031, vandetanib, and clarithromycin. CONCLUSIONS: Our study identifies unbridled turnover of the potassium channel hERG as a mechanism supporting the interindividual susceptibility underlying diLQT development and demonstrates how this phenomenon is finely tuned by CAVIN1.
Subject(s)
ERG1 Potassium Channel , Induced Pluripotent Stem Cells , Long QT Syndrome , Myocytes, Cardiac , Sotalol , Humans , Long QT Syndrome/chemically induced , Long QT Syndrome/metabolism , Long QT Syndrome/genetics , Myocytes, Cardiac/metabolism , Myocytes, Cardiac/drug effects , ERG1 Potassium Channel/genetics , ERG1 Potassium Channel/metabolism , Induced Pluripotent Stem Cells/metabolism , Induced Pluripotent Stem Cells/drug effects , Sotalol/pharmacology , Action Potentials/drug effects , Ether-A-Go-Go Potassium Channels/metabolism , Ether-A-Go-Go Potassium Channels/genetics , MaleABSTRACT
INTRODUCTION/OBJECTIVE: Studies on the use of amiodarone or sotalol are limited in dogs. Therefore, this study aimed to provide data on the efficacy and safety of these drugs in dogs with ventricular tachyarrhythmia (VT) and/or supraventricular tachyarrhythmia (SvT). ANIMALS, MATERIALS, AND METHODS: Dogs with VT and/or SvT treated with amiodarone or sotalol as a first-line therapy were retrospectively evaluated. Signalment, clinical, diagnostic, therapeutic, and outcome data were retrieved. For VT, efficacy was demonstrated through a decrease of the Lown-Wolf grade to less than five or a reduction of at least 85% in the number of ventricular premature complexes observed on Holter monitoring. For SvT, efficacy was represented by cardioversion or a reduction in the mean heart rate on Holter monitoring ≤140 beats/min. Treatment-related side effects (TRSEs) were classified as clinically relevant and irrelevant. Statistical analysis was performed to compare data before and after antiarrhythmic prescription. RESULTS: Sixty-four dogs were included. Amiodarone and sotalol were efficacious in treating both VT (85.7% and 90.0% of cases, respectively) and SvT (75% and 71.4% of cases, respectively). No significant differences were found when comparing their efficacy rates in dogs with VT and SvT (P=0.531 and 0.483, respectively). Clinically relevant TRSEs were rare with both amiodarone and sotalol (8.3% and 5% of cases, respectively), while clinically irrelevant TRSEs occurred more frequently with amiodarone (29.2%) than with sotalol (10%). DISCUSSION: In dogs with tachyarrhythmias, amiodarone and sotalol are generally efficacious and safe, as clinically relevant TRSEs seem rare. CONCLUSIONS: This study provides novel data on the effects of amiodarone and sotalol in dogs with tachyarrhythmias.
Subject(s)
Amiodarone , Anti-Arrhythmia Agents , Dog Diseases , Sotalol , Animals , Dogs , Sotalol/therapeutic use , Amiodarone/therapeutic use , Anti-Arrhythmia Agents/therapeutic use , Dog Diseases/drug therapy , Retrospective Studies , Male , Female , Treatment Outcome , Tachycardia, Ventricular/veterinary , Tachycardia, Ventricular/drug therapy , Tachycardia, Supraventricular/veterinary , Tachycardia, Supraventricular/drug therapyABSTRACT
BACKGROUND: Recurrent ventricular tachycardia (VT) in patients with prior myocardial infarction is associated with adverse quality of life and clinical outcomes, despite the presence of implanted defibrillators (ICDs). Suppression of recurrent VT can be accomplished with antiarrhythmic drug therapy or catheter ablation. The Ventricular Tachycardia Antiarrhythmics or Ablation In Structural Heart Disease 2 (VANISH2) trial is designed to determine whether ablation is superior to antiarrhythmic drug therapy as first line therapy for patients with ischemic cardiomyopathy and VT. METHODS: The VANISH2 trial enrolls patients with prior myocardial infarction and VT (with one of: ≥1 ICD shock; ≥3 episodes treated with antitachycardia pacing (ATP) and symptoms; ≥5 episodes treated with ATP regardless of symptoms; ≥3 episodes within 24 hours; or sustained VT treated with electrical cardioversion or pharmacologic conversion). Enrolled patients are classified as either sotalol-eligible, or amiodarone-eligible, and then are randomized to either catheter ablation or to that antiarrhythmic drug therapy, with randomization stratified by drug-eligibility group. Drug therapy, catheter ablation procedures and ICD programming are standardized. All patients will be followed until two years after randomization. The primary endpoint is a composite of mortality at any time, appropriate ICD shock after 14 days, VT storm after 14 days, and treated sustained VT below detection of the ICD after 14 days. The outcomes will be analyzed according to the intention-to-treat principle using survival analysis techniques RESULTS: The results of the VANISH2 trial are intended to provide data to support clinical decisions on how to suppress VT for patients with prior myocardial infarction. CLINICALTRIALS: gov registration NCT02830360.
Subject(s)
Anti-Arrhythmia Agents , Cardiomyopathies , Catheter Ablation , Myocardial Ischemia , Tachycardia, Ventricular , Humans , Tachycardia, Ventricular/therapy , Anti-Arrhythmia Agents/therapeutic use , Catheter Ablation/methods , Cardiomyopathies/complications , Cardiomyopathies/therapy , Myocardial Ischemia/complications , Male , Female , Defibrillators, Implantable , Middle Aged , Amiodarone/therapeutic use , Treatment Outcome , Sotalol/therapeutic use , Combined Modality TherapyABSTRACT
In vitro electrophysiological safety studies have become an integral part of the drug development process because, in many instances, compound-induced QT prolongation has been associated with a direct block of human ether-a-go-go-related gene (hERG) potassium channels or their native current, the rapidly activating delayed rectifier potassium current (IKr ). Therefore, according to the ICH S7B guideline, the in vitro hERG channel patch-clamp assay is commonly used as an early screen to predict the ability of a compound to prolong the QT interval prior to first-in-human testing. The protocols described in this article are designed to assess the effects of acute or long-term exposure to new chemical entities on the amplitude of IKr in HEK293 cells stably transfected with the hERG channel (whole-cell configuration of the patch-clamp technique). Examples of results obtained with moxifloxacin, terfenadine, arsenic, pentamidine, erythromycin, and sotalol are provided for illustrative purposes. © 2024 Wiley Periodicals LLC. Basic Protocol: Measurement of the acute effects of test items in the hERG channel test Alternate Protocol: Measurement of the long-term effects of test items in the hERG channel test.
Subject(s)
Ether-A-Go-Go Potassium Channels , Sotalol , Humans , Ether-A-Go-Go Potassium Channels/genetics , Patch-Clamp Techniques , HEK293 Cells , ErythromycinABSTRACT
In total, three related substances (RS) associated with sotalol hydrochloride (STHCl) were herein identified with a novel gradient high-performance liquid chromatography (HPLC) protocol. Further characterization of these substances was then performed via liquid chromatography-mass spectroscopy (LC-MS/MS) and nuclear magnetic resonance (NMR) approaches. For these analyses, commercial STHCl samples were used for quantitative HPLC studies and the degradation of STHCl under acidic (1M HCl), alkaline (1M NaOH), oxidative (30% H2O2), photolytic (4500 Lx), and thermal stress conditions (100 °C) was assessed. This approach revealed this drug to be resistant to acidic, alkaline, and high-temperature conditions, whereas it was susceptible to light and oxidation as confirmed through long-term experiments. The putative mechanisms governing RS formation were also explored, revealing that RS3 was derived from the manufacturing process, whereas RS2 was generated via oxidation and RS1 was generated in response to light exposure. The cytotoxicity of these RS compounds was then assessed using MTT assays and acute toxicity test. Overall, this study provides details regarding the characterization, isolation, quantification, and toxicological evaluation of STHCl and associated RS compounds together with details regarding the precise, specific, and reliable novel HPLC technique, thus providing the requisite information necessary to ensure STHCl purity and safety.
Subject(s)
Sotalol , Tandem Mass Spectrometry , Chromatography, High Pressure Liquid/methods , Chromatography, Liquid/methods , Sotalol/pharmacology , Tandem Mass Spectrometry/methods , Hydrogen Peroxide , Liquid Chromatography-Mass Spectrometry , Drug Stability , Hydrolysis , Oxidation-Reduction , PhotolysisABSTRACT
BACKGROUND: Loading of oral sotalol for atrial fibrillation requires 3 days, frequently in the hospital, to achieve steady state. The Food and Drug Administration approved loading with intravenous (IV) sotalol through model-informed development, without patient data. OBJECTIVE: We present results of the first multicenter evaluation of this recent labeling for IV sotalol. METHODS: The Prospective Evaluation Analysis and Kinetics of IV Sotalol (PEAKS) Registry was a multicenter observational registry of patients undergoing elective IV sotalol load for atrial arrhythmias. Outcomes, measured from hospital admission until first outpatient follow-up, included adverse arrhythmia events, efficacy, and length of stay. RESULTS: Of 167 consecutively enrolled patients, 23% were female; the median age was 68 (interquartile range, 61-74) years, and the median CHA2DS2-VASc score was 3 (interquartile range, 2-4). Overall, 99% were admitted for sotalol initiation (1% for dose escalation), with a target oral sotalol dose of either 80 mg twice daily (85 [51%]) or 120 mg twice daily (78 [47%]); 62 patients (37%) had an estimated creatinine clearance ≤90 mL/min. On presentation, 40% of patients were in sinus rhythm, whereas 26% underwent cardioversion before sotalol infusion. In 2 patients, sotalol infusion was stopped for bradycardia or hypotension. In 6 patients, sotalol was discontinued before discharge because of QTc prolongation (3), bradycardia (1), or recurrent atrial arrhythmia (2). The mean length of stay was 1.1 days, and 95% (n = 159) were discharged within 1 night. CONCLUSION: IV sotalol loading is safe and feasible for atrial arrhythmias, with low rates of adverse events, and yields shorter hospitalizations. More data are needed on the minimal duration required for monitoring in the hospital.
Subject(s)
Anti-Arrhythmia Agents , Atrial Fibrillation , Registries , Sotalol , Humans , Sotalol/administration & dosage , Female , Male , Atrial Fibrillation/drug therapy , Middle Aged , Anti-Arrhythmia Agents/administration & dosage , Aged , Prospective Studies , Dose-Response Relationship, Drug , Treatment Outcome , Infusions, Intravenous , Administration, Intravenous , Follow-Up StudiesABSTRACT
AIMS: Although guidelines for the management of atrial fibrillation (AF) are regularly published, many controversial issues remain, limiting their implementation. We aim to describe current clinical practice among European Heart Rhythm Association (EHRA) community according to last guidelines. METHODS AND RESULTS: A 30 multiple-choice questionnaire covering the most controversial topics related to AF management was distributed through the EHRA Research Network, National Societies, and social media between January and February 2023. One hundred and eighty-one physicians responded the survey, 61% from university hospitals. Atrial fibrillation screening in high-risk patients is regularly performed by 57%. Only 42% has access to at least one programme aiming at diagnosing/managing comorbidities and lifestyle modifications, with marked heterogeneity between countries. Direct oral anticoagulants are the preferred antithrombotic (97%). Rhythm control is the preferred strategy in most AF phenotypes: symptomatic vs. asymptomatic paroxysmal AF (97% vs. 77%), low vs. high risk for recurrence persistent AF (90% vs. 72%), and permanent AF (20%). I-C drugs and amiodarone are preferred while dronedarone and sotalol barely used. Ablation is the first-line therapy for symptomatic paroxysmal AF (69%) and persistent AF with markers of atrial disease (57%) and is performed independently of symptoms by 15%. In persistent AF, 68% performs only pulmonary vein isolation and 32% also additional lesions. CONCLUSION: There is marked heterogeneity in AF management and limited accordance to last guidelines in the EHRA community. Most of the discrepancies are related to the main controversial issues, such as those related to AF screening, management of comorbidities, pharmacological treatment, and ablation strategy.
Subject(s)
Atrial Fibrillation , Humans , Atrial Fibrillation/diagnosis , Atrial Fibrillation/epidemiology , Atrial Fibrillation/therapy , Comorbidity , Surveys and Questionnaires , Sotalol , Anticoagulants/therapeutic use , Treatment OutcomeABSTRACT
Ventricular tachyarrhythmias remain a major cause of sudden cardiac arrest (SCA) that leads to sudden cardiac death (SCD). Primary prevention strategies to prevent SCD include promoting a healthy lifestyle, following United States Preventive Service Task Force recommendations related to cardiovascular disease, and controlling comorbid conditions. For a patient experiencing SCA, early cardiopulmonary resuscitation and defibrillation should be performed. Implantable cardioverter defibrillators are more effective at secondary prevention compared with drug therapy but medications such as amiodarone, beta-blockers, and sotalol may be helpful adjuncts to reduce the risk of SCD or improve a patient's symptoms (eg, palpitations and inappropriate defibrillator shocks).
Subject(s)
Defibrillators, Implantable , Heart Arrest , Humans , Arrhythmias, Cardiac/therapy , Death, Sudden, Cardiac/prevention & control , Death, Sudden, Cardiac/etiology , Heart Arrest/complications , Defibrillators, Implantable/adverse effects , SotalolABSTRACT
A one-year-and-seven-month-old, 28 kg, male castrated crossbreed dog was presented for supraventricular tachycardia causing recurrent episodes of anorexia and lethargy. Sotalol (2.2 mg/kg q12 h) reduced the frequency of symptomatic episodes but did not provide full relief. Three-dimensional electroanatomical mapping was performed at the Ghent University Small Animal Teaching hospital using the CARTO 3. Right atrial activation mapping identified the earliest atrial activation right posteroseptal, near the tricuspid annulus. Fast retrograde ventriculoatrial conduction during tachycardia and extrastimulus testing confirmed the presence of a concealed right posteroseptal accessory pathway. Six radiofrequency catheter ablation applications were delivered, and tachycardia remained uninducible. The dog recovered well from the procedure. Sotalol was stopped three weeks later, and no more clinical signs were noted by the owner. Repeated 24-hour electrocardiography monitoring on day one and at one, three, and 12 months after the procedure showed no recurrence of tachycardia.
Subject(s)
Catheter Ablation , Dog Diseases , Tachycardia, Supraventricular , Humans , Male , Dogs , Animals , Heart Conduction System , Sotalol , Tachycardia, Supraventricular/diagnosis , Tachycardia, Supraventricular/surgery , Tachycardia, Supraventricular/veterinary , Tachycardia/surgery , Tachycardia/veterinary , Electrocardiography/veterinary , Catheter Ablation/veterinary , Dog Diseases/diagnostic imaging , Dog Diseases/surgeryABSTRACT
Background: Dofetilide and sotalol are potassium channel antagonists that require inpatient QTc monitoring during initiation, due to increased risk of fatal arrhythmias. Elderly patients are especially subject to an increased risk of fatal arrhythmias due to polypharmacy, comorbidities, and physiologic cardiac changes with aging. This study will describe the tolerability and risk factors associated with the initiation of sotalol or dofetilide in patients ≥80 years of age. Methodology: This is a multicenter, retrospective, descriptive study of patients ≥80 years old who were initiated on either dofetilide or sotalol between May 8, 2018 and July 31, 2021 at institutions within the Mayo Clinic Health System. The percentage of patients who received nonpackage insert recommended doses was identified. Incidence of and reasons for dose reductions or discontinuations due to safety-related events or clinical concerns during the initial loading period were collected. Results: The final analysis included 104 patients. The majority of patients (75%) received nonstandard initial doses of dofetilide or sotalol based on baseline estimated creatinine clearance or QTc. Overall, 39% (N = 41) of patients experienced a dose reduction or discontinuation due to a safety-related event or concern. Patients who received nonstandard initial doses of dofetilide or sotalol had 4.7 times greater odds of experiencing a safety-related event requiring dose reduction or discontinuation. Conclusion: Following package insert dosing in elderly patients increases safety and tolerability relative to more aggressive dosing of dofetilide or sotalol.
Subject(s)
Inpatients , Sotalol , Sulfonamides , Aged, 80 and over , Humans , Phenethylamines/adverse effects , Retrospective Studies , Sotalol/adverse effectsABSTRACT
Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a disease characterised by fibrofatty replacement of the ventricular myocardium due to specific mutations, leading to ventricular arrhythmias and sudden cardiac death. Treating this condition can be challenging due to progressive fibrosis, phenotypic variations and small patient cohorts limiting the feasibility of conducting meaningful clinical trials. Although widely used, the evidence base for anti-arrhythmic drugs is limited. Beta-blockers are theoretically sound, yet their efficacy in reducing arrhythmic risk is not robust. Additionally, the impact of sotalol and amiodarone is inconsistent with studies reporting contradictory results. Emerging evidence suggests that combining flecainide and bisoprolol may be efficacious.Radiofrequency ablation has shown some potential in disrupting ventricular tachycardia circuits, with combined endo and epicardial ablation yielding better results which could be considered at the index procedure. In addition, stereotactic radiotherapy may be a future option that can decrease arrhythmias beyond simple scar formation by altering levels of Nav1.5 channels, Connexin 43 and Wnt signalling, potentially modifying myocardial fibrosis.Future therapies, such as adenoviruses and GSk3b modulation, are still in early-stage research. While implantable cardioverter-defibrillator implantation is a key intervention for reducing arrhythmic death, the risks of inappropriate shocks and device complications must be carefully considered.
Subject(s)
Arrhythmogenic Right Ventricular Dysplasia , Defibrillators, Implantable , Tachycardia, Ventricular , Humans , Arrhythmogenic Right Ventricular Dysplasia/diagnosis , Arrhythmogenic Right Ventricular Dysplasia/therapy , Arrhythmogenic Right Ventricular Dysplasia/complications , Arrhythmias, Cardiac/complications , Anti-Arrhythmia Agents/therapeutic use , Death, Sudden, Cardiac/etiology , Death, Sudden, Cardiac/prevention & control , Sotalol , Tachycardia, Ventricular/diagnosis , Tachycardia, Ventricular/etiology , Tachycardia, Ventricular/therapy , Defibrillators, Implantable/adverse effectsABSTRACT
INTRODUCTION/OBJECTIVES: The objective of this study was to describe the single- and multiple-dose pharmacokinetics and urinary elimination of sotalol in healthy cats. ANIMALS: Six adult purpose-bred cats MATERIALS AND METHODS: Cats were administered 2 mg sotalol/kg body weight as a single intravenous bolus and as a single oral dose in a randomized crossover study with a two-week washout period. The same cats then received 3 mg sotalol/kg orally every 12 h for two weeks. Blood samples were collected at predetermined time points for 48 h postdose for quantification of sotalol using ultra-high-pressure liquid chromatography with mass spectrometry. Non-compartmental analysis was used to obtain pharmacokinetic parameters. Data are presented as median (min-max). RESULTS: Following intravenous administration, plasma clearance and volume of distribution were 9.22 mL/min/kg (5.69-10.89 mL/min/kg) and 2175.56 mL/kg (1961-2341.57 mL/kg), respectively. Bioavailability was 88.41% (62.75-130.29) following a single oral dose. Peak plasma concentration (Cmax) and time to Cmax were 0.94 µg/mL (0.45-1.17 µg/mL) and 1.5 h (0.5-4 h) after a single oral dose (2 mg/kg), and 2.29 µg/mL (1.91-2.48 µg/mL) and 1.0 h (0.5-1.5 h) with chronic oral dosing (3 mg/kg), respectively. Elimination half-life was 2.75 h (2.52-4.10 h) and 4.29 h (3.33-5.53 h) for single and chronic oral dosing, respectively. Accumulation index was 1.17 (1.09-1.29) after chronic dosing. Urinary sotalol recovery was 81-108% of the intravenous dose. CONCLUSIONS: Oral sotalol administration resulted in plasma concentrations reportedly efficacious in other species, with good to excellent oral bioavailability. Urinary excretion appears to be a major route of elimination. Following repeated oral dosing, minimal drug accumulation was estimated. Additional studies in cats are recommended due to the possibility of nonlinear kinetics.
Subject(s)
Sotalol , Cats , Animals , Cross-Over Studies , Infusions, Intravenous/veterinary , Chromatography, High Pressure Liquid/veterinary , Biological Availability , Administration, Oral , Half-LifeABSTRACT
This chapter discusses the American College of Cardiology/American Heart Association/ Heart Rhythm Society (AHA/ACC/HRS) and European Society of Cardiology (ESC) guidelines for atrial fibrillation (AF) management with particular focus on antiarrhythmic drug (AAD) selection and the identification of individuals for whom AAD treatment is appropriate. Discussion includes AAD indications, when to start an AAD, choosing among AADs, how to minimize proarrhythmic risk, how to determine efficacy, and the use of adjuvant interventions. The indications for all AADs are based on safety; the current AHA/ACC/HRS and ESC guidelines state that the choice of AAD is based on the presence or absence of structural heart disease (SHD), coronary artery disease, or heart failure (HF), with further recommendations in the ESC guidelines based on HF type (e.g., HF with reduced ejection fraction [HFrEF] versus HF with preserved ejection fraction [HFpEF]). The chapter closes with a discussion of the lack of consistent use of guideline-directed care, with a review of supportive data from the recently reported AIM-AF survey-a multinational survey on AF management that involved both cardiologists and electrophysiologists. In AIM-AF, inappropriate drug selection in terms of suitable candidate selection and drug choice occurred with all types of drugs and in most patient groups. Most notable was the overuse of amiodarone in patients without SHD, and the widespread use of sotalol, including its use in patients with HFrEF. Chapter 5 is summarized as follows.
Subject(s)
Atrial Fibrillation , Heart Failure , Humans , Anti-Arrhythmia Agents/therapeutic use , Atrial Fibrillation/drug therapy , Heart Failure/drug therapy , Sotalol/therapeutic use , Stroke Volume , United StatesABSTRACT
BACKGROUND: Beta-blockers (BB) or dihydropyridine calcium channel blockers (CCBs) are still the first choices in the treatment of idiopathic premature ventricular complexes (PVCs), with low-modest efficacy. Antiarrhythmic drugs (AADs) of Ic class are moderate to highly efficient but the evidence on their benefits is still limited. AIM: To compare effectiveness and safety of flecainide, propafenone, and sotalol in the treatment of symptomatic idiopathic PVCs. METHODS: Our single-center retrospective study analyzed 104 consecutive patients with 130 medication episodes of frequent idiopathic PVCs treated with AADs flecainide, propafenone (Ic class) or sotalol (III class). The primary outcome was complete/near complete reduction of PVCs after medication episode (PVCs burden reduction >99%), and the secondary outcome was significant PVC burden reduction (≥80%). RESULTS: The complete/near complete PVCs burden reduction occurred in 31% and was significant in 43% of treated patients. A reduction of PVC burden for >99% was achieved in 56% of patients on flecainide, in 11% of patients on propafenone (p = .002), and in 21% of patients receiving sotalol (p = .031). There was no difference between propafenone and sotalol (p = .174). A reduction of PVC burden for ≥80% was achieved in 64% of patients on flecainide, in 30% of patients on propafenone (p = .009), and 33% of patients on sotalol (p = .020). There was no difference between propafenone and sotalol (p = .661). CONCLUSIONS: The efficacy of AADs class Ic and III in the treatment of idiopathic PVCs was modest. Flecainide was the most effective AAD in the achievement of complete/near complete or significant PVC burden reduction, compared to propafenone and sotalol.
Subject(s)
Propafenone , Ventricular Premature Complexes , Humans , Propafenone/adverse effects , Flecainide/adverse effects , Sotalol/adverse effects , Retrospective Studies , Electrocardiography , Anti-Arrhythmia Agents/adverse effects , Ventricular Premature Complexes/diagnosis , Ventricular Premature Complexes/drug therapyABSTRACT
BACKGROUND: Use of d,l-sotalol for rhythm control in patients with atrial fibrillation (AF) has raised safety concerns. Previous randomized studies are few and not designed for mortality outcome. OBJECTIVE: The purpose of this study was to compare the incidences of mortality and ventricular arrhythmias in AF patients treated with d,l-sotalol for rhythm control vs matched control patients treated with cardioselective beta-blockers. METHODS: This population-based cohort study included AF patients from the Swedish National Patient Registry (2006-2017) who underwent rhythm control after a second cardioversion. Incidence rates (IRs) and adjusted hazard ratios (aHRs) for mortality and a composite endpoint of cardiac arrest/death and ventricular arrhythmias were calculated for the overall cohort and a 1:1 propensity score matched cohort of d,l-sotalol vs beta-blocker treatment. RESULTS: Among patient treated with d,l-sotalol (n = 4987) and beta-blocker (n = 27,078) (mean follow-up 458 days), all-cause mortality was lower in patients treated with d,l-sotalol: IR 1.21; 95% confidence interval 0.95-1.52 vs 2.42 (2.26-2.60) deaths per 100 patient-years; aHR 0.66 (0.52-0.83). The difference in mortality persisted in the propensity score matched comparison (n = 4953 in each group): aHR 0.63 (0.48-0.86). No differences were observed in the composite outcome: IR in propensity cohorts 2.13 (1.78-2.52) vs 2.07 (1.73-2.53) events per 100 years; aHR 1.01 (0.78-1.29). CONCLUSION: There was no excess mortality with d,l-sotalol compared with cardioselective beta-blockers in patients undergoing rhythm control treatment for AF after a second cardioversion. Our results indicate that the risk associated with d,l-sotalol treatment for AF can be mitigated by careful patient selection and strict adherence to follow-up protocols.
Subject(s)
Atrial Fibrillation , Sotalol , Humans , Sotalol/therapeutic use , Atrial Fibrillation/complications , Atrial Fibrillation/drug therapy , Anti-Arrhythmia Agents/therapeutic use , Cohort Studies , Adrenergic beta-Antagonists/therapeutic useABSTRACT
BACKGROUND: Sotalol and dronedarone are both used for maintenance of sinus rhythm for patients with atrial fibrillation. However, while sotalol requires initial monitoring for QT prolongation and proarrhythmia, dronedarone does not. These treatments can be used in comparable patients, but their safety and effectiveness have not been compared head to head. Therefore, we retrospectively evaluated the effectiveness and safety using data from a large health care system. METHODS: Using Veterans Health Administration data, we identified 11 296 antiarrhythmic drug-naive patients with atrial fibrillation prescribed dronedarone or sotalol in 2012 or later. We excluded patients with prior conduction disease, pacemakers or implantable cardioverter-defibrillators, ventricular arrhythmia, cancer, renal failure, liver disease, or heart failure. We used natural language processing to identify and compare baseline left ventricular ejection fraction between treatment arms. We used 1:1 propensity score matching, based on patient demographics, comorbidities, and medications, and Cox regression to compare strategies. To evaluate residual confounding, we performed falsification analysis with nonplausible outcomes. RESULTS: The matched cohort comprised 6212 patients (3106 dronedarone and 3106 sotalol; mean [±SD] age, 71±10 years; 2.5% female; mean [±SD] CHA2DS2-VASC, 2±1.3). The mean (±SD) left ventricular ejection fraction was 55±11 and 58±10 for dronedarone and sotalol users, correspondingly. Dronedarone, compared with sotalol, did not demonstrate a significant association with risk of cardiovascular hospitalization (hazard ratio, 1.03 [95% CI, 0.88-1.21]) or all-cause mortality (hazard ratio, 0.89 [95% CI, 0.68-1.16]). However, dronedarone was associated with significantly lower risk of ventricular proarrhythmic events (hazard ratio, 0.53 [95% CI, 0.38-0.74]) and symptomatic bradycardia (hazard ratio, 0.56 [95% CI, 0.37-0.87]). The primary findings were stable across sensitivity analyses. Falsification analyses were not significant. CONCLUSIONS: Dronedarone, compared with sotalol, was associated with a lower risk of ventricular proarrhythmic events and conduction disorders while having no difference in risk of incident cardiovascular hospitalization and mortality. These observational data provide the basis for prospective efficacy and safety trials.
Subject(s)
Amiodarone , Atrial Fibrillation , Veterans , Female , Humans , Middle Aged , Aged , Aged, 80 and over , Male , Anti-Arrhythmia Agents/adverse effects , Dronedarone/adverse effects , Sotalol/adverse effects , Atrial Fibrillation/diagnosis , Atrial Fibrillation/drug therapy , Atrial Fibrillation/chemically induced , Retrospective Studies , Prospective Studies , Stroke Volume , Ventricular Function, Left , Amiodarone/adverse effectsABSTRACT
Aim: To evaluate the clinical and economic impact of antiarrhythmic drugs (AADs) compared with ablation both as individual treatments and as combination therapy without/with considering the order of treatment among patients with atrial fibrillation (AFib). Materials & methods: A budget impact model over a one-year time horizon was developed to assess the economic impact of AADs (amiodarone, dofetilide, dronedarone, flecainide, propafenone, sotalol, and as a group) versus ablation across three scenarios: direct comparisons of individual treatments, non-temporal combinations, and temporal combinations. The economic analysis was conducted in accordance with CHEERS guidance as per current model objectives. Results are reported as costs per patient per year (PPPY). The impact of individual parameters was evaluated using one-way sensitivity analysis (OWSA). Results: In direct comparisons, ablation had the highest annual medication/procedure cost ($29,432), followed by dofetilide ($7661), dronedarone ($6451), sotalol ($4552), propafenone ($3044), flecainide ($2563), and amiodarone ($2538). Flecainide had the highest costs for long-term clinical outcomes ($22,964), followed by dofetilide ($17,462), sotalol ($15,030), amiodarone ($12,450), dronedarone ($10,424), propafenone ($7678) and ablation ($9948). In the non-temporal scenario, total costs incurred for AADs (group) + ablation ($17,278) were lower compared with ablation alone ($39,380). In the temporal scenario, AADs (group) before ablation resulted in PPPY cost savings of ($22,858) compared with AADs (group) after ablation ($19,958). Key factors in OWSA were ablation costs, the proportion of patients having reablation, and withdrawal due to adverse events. Conclusion: Utilization of AADs as individual treatment or in combination with ablation demonstrated comparable clinical benefits along with costs savings in patients with AFib.