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Background: Atrial fibrillation is the most prevalent cardiac arrhythmia, presenting symptomatic patients with diminished quality of life and worsening of heart failure. Dofetilide, a class 3 antiarrhythmic agent, is a proven and safe rhythm control medication. Initial risk of QT prolongation leading to torsade de pointes (TdP) necessitates a standard protocol mandating hospitalization for three days for initiation. Objectives: To assess safety when adhering to initiation protocol and identify traits for susceptibility to TdP in elective dofetilide admissions. Methods: We conducted a retrospective study involving patients admitted to Mayo Clinic sites across four states for elective inpatient initiation of dofetilide between 2003 and 2022. Patients’ charts underwent review, focusing on dofetilide-related TdP occurrences, baseline characteristics including QT intervals, laboratory values, comorbidities, and concomitant medications. Patients who experienced TdP were subjected to further evaluation to identify potential risk factors. Results: Of 2036 patients identified, mean age 66.4 ± 11.4 years, and 67.2 % male, 16 experienced dofetilide-related TdP (incidence rate 0.79%). Notably, 81% (13/16) of TdP cases occurred in patients who deviated from the FDA/manufacturer algorithm protocol. The concomitant use of active intravenous diuretic therapy, digoxin, and QT-prolonging drugs emerged as identifiable risk factors. Additionally, females exhibited a higher incidence of TdP (1.5%) than males (0.44%) {odd ratio [OR] 3.46; P = 0.017}. Conclusion: Overall incidence of TdP related to dofetilide initiation was low (0.79%). Adherence to protocol during elective hospital admissions appears extraordinarily safe. Patients who did not require concurrent use of intravenous diuretics, digoxin, or QT prolonging drugs exhibited lower risk of TdP.

Despite decades of research, heart disease remains a burden on global health, especially in developed countries. Among problematic cardiovascular indications, abnormal heart rhythms or arrhythmias play a significant role. Dofetilide is a unique cardiovascular drug and one of the earliest antiarrhythmic agents. For many years, compounds labelled with tritium have been extremely useful to facilitate drug discovery research at the receptor level. This paper describes the tritium labelling of dofetilide by several methods. The syntheses and characterization of [phenyl-3H] dofetilide as well as [N-methyl-3H] dofetilide are described in detail. ESI mass spectrometry was found to be an especially useful analytical tool to characterize these valuable radioligands. Because of synthetic efficiency and high specific activity, [N-methyl-3H] dofetilide emerged as the preferred radioligand used by biologists worldwide and information about its storage and stability are also discussed. [ABSTRACT FROM AUTHOR]

Background or Purpose: To assess effectiveness of dofetilide in reducing the burden of ventricular arrhythmias (VAs). Background: Prior small sample studies show that dofetilide has benefit in reducing VA. However, large sample investigations with long-term follow-up are lacking. Methods: Two hundred seventeen consecutive patients admitted between January 2015 and December 2021 for dofetilide initiation for control of VA were assessed. Dofetilide was successfully started in 176 patients (81%) and had to be discontinued in the remaining 41 patients (19%). Dofetilide was initiated for control of ventricular tachycardia (VT) in 136 patients (77%), whereas 40 (23%) patients were initiated on dofetilide for reducing the burden of premature ventricular complexes (PVCs). Results: The mean follow-up was 24 ± 7 months. In total, among the 136 VT patients, 33 (24%) died, 11 (8%) received a left ventricular assist device (LVAD), and 3 (2%) received a heart transplant during follow-up. Dofetilide was discontinued in 117 (86%) patients due to lack of sustained effectiveness during follow-up. Dofetilide use was associated with similar odds of the composite outcome of all-cause mortality/LVAD/heart transplant (OR: 0.97, 0.55–4.23) in patients with ischemic cardiomyopathy (ICM) compared to those with non-ischemic cardiomyopathy (NICM). Dofetilide did not reduce PVC burden during follow-up in the 40 patients with PVCs (mean baseline PVC burden: 15%, at 1-year follow-up: 14%). Conclusions: Dofetilide use was less effective in reducing VA burden in our cohort of patients. Randomized controlled studies are needed to confirm our findings. [ABSTRACT FROM AUTHOR]

Background: Initiation of dofetilide requires hospital admission because of its proarrhythmic risk. To reduce the risk of adverse events associated with dofetilide, our institution has a standard operating protocol for dofetilide initiation. Regardless, patients are sometimes admitted for dofetilide initiation with unaddressed pharmacotherapy concerns that may delay therapy initiation and/or increase the risk for adverse events. Objective: To characterize interventions associated with pharmacist evaluation of scheduled dofetilide admissions prior to hospitalization. Methods: Patients scheduled for dofetilide initiation were evaluated by a pharmacist prior to admission. Identified interventions were categorized into the following recommendations: (1) against the use of dofetilide; (2) dofetilide starting dose adjustment; (3) appropriate washout of previous antiarrhythmic drug; (4) transesophageal echocardiogram prior to dofetilide initiation; (5) discontinuation or dose adjustment of interacting drug; (6) electrolyte supplementation upon discharge; (7) other intervention. The primary outcome measure was the frequency and types of identified and accepted interventions. Results: Twenty-two patients were evaluated during the 9-month study period. Fourteen interventions were identified, 13 of which were accepted by an electrophysiology provider. The most common intervention was for recommendation of a transesophageal echocardiogram prior to initiating dofetilide because of inadequate oral anticoagulation (n = 6). Other accepted interventions were for discontinuation or dose adjustment of interacting drug (n = 3), dofetilide starting dose adjustment (n = 2), electrolyte supplementation upon discharge (n = 2), and remeasurement of interventricular septal wall thickness (n = 1). Conclusion: Pharmacist evaluation of scheduled dofetilide admissions prior to hospitalization can serve to identify and resolve pharmacotherapy concerns related to dofetilide use. [ABSTRACT FROM AUTHOR]

Purpose: Since atrial fibrillation (AF) is one of the major arrhythmias managed in hospitals worldwide, it has a major impact on public health. The guidelines agree on the desirability of cardioverting paroxysmal AF episodes. This meta-analysis aims to answer the question of which antiarrhythmic agent is most effective in cardioverting a paroxysmal AF. Materials and Methods: A systematic review and Bayesian network meta-analysis, searching MEDLINE, Embase, and CINAHL, were performed, including randomized controlled trials (RCTs) enrolling a population of unselected adult patients with a paroxysmal AF that compared at least two pharmacological regimes to restore the sinus rhythm or a cardioversion agent against a placebo. The main outcome was efficacy in restoring sinus rhythm. Results: Sixty-one RCTs (7988 patients) were included in the quantitative analysis [deviance information criterion (DIC) 272.57; I2 = 3%]. Compared with the placebo, the association verapamil–quinidine shows the highest SUCRA rank score (87%), followed by antazoline (86%), vernakalant (85%), tedisamil at high dose (i.e., 0.6 mg/kg; 80%), amiodarone–ranolazine (80%), lidocaine (78%), dofetilide (77%), and intravenous flecainide (71%). Taking into account the degree of evidence of each individual comparison between pharmacological agents, we have drawn up a ranking of pharmacological agents from the most effective to the least effective. Conclusions: In comparing the antiarrhythmic agents used to restore sinus rhythm in the case of paroxysmal AF, vernakalant, amiodarone–ranolazine, flecainide, and ibutilide are the most effective medications. The verapamil–quinidine combination seems promising, though few RCTs have studied it. The incidence of side effects must be taken into account in the choice of antiarrhythmic in clinical practice. Clinical Trial Registration: PROSPERO: International prospective register of systematic reviews, 2022, CRD42022369433 (Available from: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42022369433). [ABSTRACT FROM AUTHOR]

Drug-induced QT prolongation (DI-QTP) is a clinical entity in which administration of a human ether-à-go-go–related gene/rapid delayed rectifier potassium current blocker such as dofetilide prolongs the cardiac action potential duration (APD) and the QT interval on the electrocardiogram. Inhibition of serum and glucocorticoid regulated kinase-1 (SGK1) reduces the APD at 90% repolarization (APD90) in induced pluripotent stem cell–derived cardiomyocytes (iPSC-CMs) derived from patients with congenital long QT syndrome. Here, we test the efficacy of 2 novel SGK1 inhibitors—SGK1-I1 and SGK1-I2—in iPSC-CM models of dofetilide-induced APD prolongation. Normal iPSC-CMs were treated with dofetilide to produce a DI-QTP iPSC-CM model. SGK1-I1's and SGK1-I2's therapeutic efficacy for shortening the dofetilide-induced APD90 prolongation was compared to mexiletine. The APD90 values were recorded 4 hours after treatment using a voltage-sensing dye. The APD90 was prolonged in normal iPSC-CMs treated with dofetilide (673 ± 8 ms vs 436 ± 4 ms; P <.0001). While 10 mM mexiletine shortened the APD90 of dofetilide-treated iPSC-CMs from 673 ± 4 to 563 ± 8 ms (46% attenuation; P <.0001), 30 nM of SGK1-I1 shortened the APD90 from 673 ± 8 to 502 ± 7 ms (72% attenuation; P <.0001). Additionally, 300 nM SGK1-I2 shortened the APD90 of dofetilide-treated iPSC-CMs from 673 ± 8 to 460 ± 7 ms (90% attenuation; P <.0001). These novel SGK1-Is substantially attenuated the pathological APD prolongation in a human heart cell model of DI-QTP. These preclinical data support the development of this therapeutic strategy to counter and neutralize DI-QTP, thereby increasing the safety profile for patients receiving drugs with torsadogenic potential. [ABSTRACT FROM AUTHOR]

Background: Left ventricular hypertrophy (LVH) is common in patients with atrial fibrillation (AF), however, many antiarrhythmic drugs (AADs) are contraindicated. US guidelines recommend avoiding pure class III antiarrhythmics such as dofetilide in patients with significant LVH due to concern for an increased risk of death, however, clinical data is lacking. We sought to determine if dofetilide use was associated with increased mortality in patients with LVH. Methods: Patients ≥18 years of age with AF and LVH ≥ 1.4 cm were included. A group of patients treated with dofetilide and a control group of patients without a history of AAD use were propensity matched. The primary outcome was all‐cause mortality at 3 years and secondary outcomes were total number of all‐cause hospitalizations and hospitalizations related to AF. Results: There were 359 patients in each of the groups. Baseline variables were well‐matched. The primary outcome of all‐cause mortality occurred in 7% of patients in the dofetilide group and 12% of patients in the control group (hazard ratio: 0.90, 95% confidence interval: 0.53–1.53). Total all‐cause hospitalizations were higher in the control group but hospitalizations for AF were no different. Conclusions: In a propensity‐matched cohort of 718 patients with AF and LVH, dofetilide was not associated with increased mortality at 3 years. Our study adds to prior data demonstrating the safety of dofetilide in this population despite guideline recommendations against its use. Given the limited options for AF management in LVH patients, dofetilide may be reasonable for symptomatic AF management. [ABSTRACT FROM AUTHOR]

The complexation an anti-arrhythmia drug dofetilide (DFT) with β-cyclodextrin (β-CD), 2-hydroxypropyl-β-cyclodextrin (HP-β-CD) and sulfobutylether-β-cyclodextrin (SBE-β-CD) were studied using two main approaches: phase solubility diagrams and solid dispersions technique. The phase solubility diagrams were constructed in buffer solutions with physiological values рН 2.0 и 7.4. In accordance with the protolytic properties of the drug, the solubilizing effect of cyclodextrins turned out to be more effective in a neutral environment (buffer pH 7.4): the solubility improvement of DFT in the presence of β-CD, HP-β-CD and SBE-β-CD was 3.6, 11.8 and 18.1 times, respectively. In buffer pH 2.0, the tendency for an increase in the solubilizing effect, depending on the chemical nature of the CDs used, is maintained, but the solubility of the drug almost does not grow. The binding constants for the DFT/HP-β-CD and DFT/SBE-β-CD complexes equal to 344 L·mol−1 and 429 L·mol−1 in buffer pH 7.4 indicate the formation of stable inclusion complexes and belong to the optimal range for refinement bioavailability and stability of hydrophobic drugs. Amorphous solid dispersions DFT/β-CD, DFT/HP-β-CD and DFT/SBE-β-CD with stoichiometry 1:1 were obtained by grinding method. The combination FTIR, PXRD, DSC, TGA and SEM methods confirmed the inclusion complexes formation of the drug with cyclodextrins used. Dissolution profiles of solid dispersions DFT/β-CD, DFT/HP-β-CD and DFT/SBE-β-CD were graphing in buffer solutions рН 2.0 and 7.4. Enlargement factor of DFT solubility in the composition of solid dispersions DFT/β-CD, DFT/HP-β-CD and DFT/SBE-β-CD in the neutral medium are 3.4, 4.1 and 5.2, respectively. Whereas the formation of solid inclusion complexes DFT/CDs in an acidic buffer has virtually no effect on the increase in the equilibrium concentration of the active substance in the solution. Findings have demonstrated that the use of SBE-β-CD shows the best solubilization potential for DFT both in solution and as a solid dispersion. [Display omitted] [ABSTRACT FROM AUTHOR]

Antiarrhythmic drugs (AADs) and catheter ablation (CA) are guideline-directed rhythm control treatment for atrial fibrillation (AF). AADs are rarely used in combination to treat AF. Dofetilde (class III agent) and flecainide (class Ic agent) are contraindicated in patients with renal dysfunction and coronary artery disease respectively. We describe a case of a patient who refused non-pharmacological treatment for recurrent AF after CA, but was treated successfully with dofetilide and flecainide combination. The patient's taking the combination was serendipitous initially. Both drugs were continued nonetheless, as it was the combination and not the individual drug that controlled AF in our patient., (Copyright © 2024. Published by Elsevier Inc.)

Background: Dofetilide is a class III antiarrhythmic agent approved for the treatment of atrial fibrillation and atrial flutter. Given the efficacy of other class III agents, it has been used off-label for the treatment of premature ventricular complexes (PVCs) and ventricular tachycardias (VTs)., Objective: The purpose of this study was to determine the efficacy and safety of dofetilide for ventricular arrythmias (VAs)., Methods: In this retrospective cohort study, 81 patients (59 men; age = 60 ± 14 years; LVEF = 0.34 ± 0.16) were admitted for dofetilide initiation to treat PVCs (29), VTs (42) or both (10). A ≥ 80% decrease in PVC burden was defined as a satisfactory response. An ICD was present in 72 patients (89%). Another antiarrhythmic was previously used in 50 patients (62%). Prior catheter ablation had been performed in 33 patients (41%)., Results: During intitiation, dofetilide was discontinued in 12 patients (15%) due to QT prolongation (8) and inefficacy to suppress VAs (4). Among the 32 patients with PVCs who successfully started dofetilide, the mean PVC burden decreased from 20 ± 10% to 8 ± 8% at a median follow-up of 2.6 months (p < .001). PVC burden was reduced by ≥80% in only 11/32 patients (34%). During 7 ± 1 years of follow-up, 41/69 patients (59%) continued to have VAs and received appropriate ICD therapies for monomorphic VTs (35) and polymorphic VT/VF (6) at a median of 8.0 (IQR 2.6-33.2) months. Dofetilide had to be discontinued in 50/69 patients (72%) due to inefficacy or intolerance. The composite outcome of VT/VF recurrence, heart transplantation, or death occurred in 6/12 patients (50%) without dofetilide and 49/69 patients (71%) with dofetilide. The event free survival was similar between patients treated with and without dofetilide (log-rank p = .55)., Conclusions: Treatment with dofetilide was associated with a decrease in PVCs, however clinically significant suppression occurred in a minority of patients. Dofetilide failed to suppress the occurrence of VTs in a majority of patients., (© 2024 The Author(s). Journal of Cardiovascular Electrophysiology published by Wiley Periodicals LLC.)

Introduction: Dofetilide is an antiarrhythmic medication that has the potential to cause life threatening arrhythmias, such as Torsade de pointes. The 2014 ACC/AHA/HRS guidelines for the management of patients with atrial fibrillation state that patients need to meet certain criteria to be initiated on dofetilide. Patients who are not initiated on this therapy according to the guideline criteria are likely to be at higher risk of adverse reactions. Methods: This is a single center, retrospective chart review of patients who were initiated on dofetilide from July 2016-December 2019. Patients included in the study were initiated on dofetilide as a new antiarrhythmic and monitored inpatient for 3 days. The primary outcome was a composite of incidence of cardiac arrhythmias, cardiac arrest, cardiac death, and cardiac related hospital readmission. Results: There were 224 patients included in the analysis: 190 patients who were initiated on dofetilide inappropriately and 34 that were initiated appropriately. The primary outcome (composite of cardiac arrhythmia, cardiac arrest, cardiac death, and hospital readmission) was statistically significant with more patients experiencing an outcome in the group initiated inappropriately. Conclusions: Patients are placed at a higher risk of adverse reactions when this potentially dangerous antiarrhythmic medication is not used according to the protocol set forth by the guidelines. Practitioners should use caution when prescribing dofetilide. Other antiarrhythmic medications or non-pharmacologic options should be considered due to the incidence of these dangerous adverse reactions. [ABSTRACT FROM AUTHOR]

Dofetilide is a rapid delayed rectifier potassium current inhibitor widely used to prevent the recurrence of atrial fibrillation and flutter. The clinical use of this drug is associated with increases in QTc interval, which predispose patients to ventricular cardiac arrhythmias. The mechanisms involved in the disposition of dofetilide, including its movement in and out of cardiomyocytes, remain unknown. Using a xenobiotic transporter screen, we identified MATE1 (SLC47A1) as a transporter of dofetilide and found that genetic knockout or pharmacological inhibition of MATE1 in mice was associated with enhanced retention of dofetilide in cardiomyocytes and increased QTc prolongation. The urinary excretion of dofetilide was also dependent on the MATE1 genotype, and we found that this transport mechanism provides a mechanistic basis for previously recorded drug-drug interactions of dofetilide with various contraindicated drugs, including bictegravir, cimetidine, ketoconazole, and verapamil. The translational significance of these observations was examined with a physiologically-based pharmacokinetic model that adequately predicted the drug-drug interaction liabilities in humans. These findings support the thesis that MATE1 serves a conserved cardioprotective role by restricting excessive cellular accumulation and warrant caution against the concurrent administration of potent MATE1 inhibitors and cardiotoxic substrates with a narrow therapeutic window. [ABSTRACT FROM AUTHOR]

Introduction: Dofetilide suppresses atrial fibrillation (AF) in a dose‐dependent fashion. The protective effect of AF against QTc prolongation induced torsades de pointe and transient post‐cardioversion QTc prolongation may result in dofetilide under‐dosing during initiation. Thus, the optimal timing of cardioversion for AF patients undergoing dofetilide initiation to optimize discharge dose remains unknown as does the longitudinal stability of QTc. The purpose of this study was to evaluate the impact of baseline rhythm on dofetilide dosing during initiation and assess the longitudinal stability of QTc‐all (Bazzett, Fridericia, Framingham, and Hodges) over time. Methods: Medical records of patients who underwent preplanned dofetilide loading at a tertiary care center between January 2016 and 2019 were reviewed. Results: A total of 198 patients (66 ± 10 years, 32% female, CHADS2‐Vasc 3 [2–4]) presented for dofetilide loading in either AF (59%) or sinus rhythm (SR) (41%). Neither presenting rhythm, nor spontaneous conversion to SR impacted discharge dose. The cumulative dofetilide dose before cardioversion moderately correlated (r =.36; p =.0001) with discharge dose. Postcardioversion QTc‐all prolongation (p <.0001) prompted discharge dose reduction (890 ± 224 mcg vs. 552 ± 199 mcg; p <.0001) in 30% patients. QTc‐all in SR prolonged significantly during loading (p <.0001). All patients displayed QTc‐all reduction (p <.0001) from discharge to short‐term (46 [34–65] days) that continued at long‐term (360 [296–414] days) follow‐ups. The extent of QTc‐all reduction over time moderately correlated with discharge QTc‐all (r =.54–0.65; p <.0001). Conclusion: Dofetilide initiation before cardioversion is equivalent to initiation during SR. Significant QTc reduction proportional to discharge QTc is seen over time in all dofetilide‐treated patients. QTc returns to preloading baseline during follow‐up in patients initiated in SR. [ABSTRACT FROM AUTHOR]

Key pointsThis study represents a first step toward predicting mechanisms of sex-based arrhythmias that may lead to important developments in risk stratification and may inform future drug design and screening. We undertook simulations to reveal the conditions (i.e. pacing, drugs, sympathetic stimulation) required for triggering and sustaining reentrant arrhythmias. Using the recently solved cryo-EM structure for the Eag-family channel as a template, we revealed potential interactions of oestrogen with the pore loop hERG mutation (G604S). Molecular models suggest that oestrogen and dofetilide blockade can concur simultaneously in the hERG channel pore.AbstractFemale sex is a risk factor for inherited and acquired long-QT associated torsade de pointes (TdP) arrhythmias, and sympathetic discharge is a major factor in triggering TdP in female long-QT syndrome patients. We used a combined experimental and computational approach to predict 'the perfect storm' of hormone concentration, IKr block and sympathetic stimulation that induces arrhythmia in females with inherited and acquired long-QT. More specifically, we developed mathematical models of acquired and inherited long-QT syndrome in male and female ventricular human myocytes by combining effects of a hormone and a hERG blocker, dofetilide, or hERG mutations. These 'male' and 'female' model myocytes and tissues then were used to predict how various sex-based differences underlie arrhythmia risk in the setting of acute sympathetic nervous system discharge. The model predicted increased risk for arrhythmia in females when acute sympathetic nervous system discharge was applied in the settings of both inherited and acquired long-QT syndrome. Females were predicted to have protection from arrhythmia induction when progesterone is high. Males were protected by the presence of testosterone. Structural modelling points towards two plausible and distinct mechanisms of oestrogen action enhancing torsadogenic effects: oestradiol interaction with hERG mutations in the pore loop containing G604 or with common TdP-related blockers in the intra-cavity binding site. Our study presents findings that constitute the first evidence linking structure to function mechanisms underlying female dominance of arousal-induced arrhythmias.

Nonclinical evaluation of the cardiovascular effects of novel chemical or biological entities (NCE, NBEs) is crucial for supporting first-in-human clinical trials. One important aspect of these evaluations is the assessment of potential QT/QTc prolongation risk, as drug-induced QT prolongation can have catastrophic effects. The recent publication of E14/S7B Q&As allows for the situational incorporation of nonclinical QTc data as part of an integrated risk assessment for a Thorough QT (TQT) waiver application provided certain best practice criteria are met. Recent publications provided detailed characterization of nonclinical QTc telemetry data collected from the commonly used Latin square study design. To understand whether data from alternate telemetry study designs were sufficient to serve as part of the E14/S7B integrated risk assessment, we report the performance and translational sensitivity to identify clinical risk of QTc prolongation risk for an ascending dose telemetry design. The data demonstrated low variability in QTci interval within animals from day to day, indicating a well-controlled study environment and limited concern for uncontrolled effects across dosing days. Historical study variances of the ascending dose design with n = 4 subjects, measured by least significant difference (LSD) and root mean square error (RMSE) values, were low enough to detect a + 10 ms QTci interval change, and the median minimum detectable difference (MDD) for QTci interval changes was <10 ms. Furthermore, concentration-QTci (C-QTci) assessments to determine +10 ms QTci increases for known hERG inhibitors were comparable to clinical CC values listed in the E14/S7B training materials, supporting the use of the ascending dose design in an E14/S7B integrated risk assessment. These findings suggest that the ascending dose design can be a valuable tool in nonclinical evaluation of QT/QTc prolongation risk and the support of TQT waiver applications. [ABSTRACT FROM AUTHOR]

Managing the risks and consequences of long QT syndrome can be challenging. Multiple factors contribute to the prolongation of the heart-rate corrected QT (QTc) interval including many drug-drug and drug-disease state interactions. Current literature is often focused on avoiding dysrhythmias with limited guidance on acute management strategies. Here we describe a case of QTc prolongation to 616 msec (Bazett's formula) in the setting of chronic dofetilide overdose due to a possible prescription error. Our case was complicated by alcohol withdrawal and electrolyte disturbances that progressed to patient cardiac arrest in the emergency department. Dofetilide overdose was identified through pharmacist-initiated medication reconciliation and lidocaine was recommended as an alternative to amiodarone during advanced cardiac life support (ACLS). This case highlights the importance of reviewing outpatient medication records as well as avoiding drug-drug interactions during ACLS. Due to the potential for additive QTc prolongation, we recommend using lidocaine as the preferred antiarrhythmic in ACLS algorithms where drug induced QTc prolongation is suspected. [ABSTRACT FROM AUTHOR]

Background: At peak COVID-19 lockdown, patients with symptomatic atrial fibrillation (AF) were faced with an equipoise between a palliative rate-control versus cautious rhythm-control strategy, including hospitalization for initiation of antiarrhythmic drug/s (AADs) and cardiac procedures which was impossible due to hospitalization restrictions. Objectives: We aimed to evaluate the efficacy and safety of outpatient initiation of dofetilide in patients with AF using cardiac implantable electronic devices (CIEDs) for rhythm and QTc interval monitoring. Methods: Adult patients with symptomatic AF with prior failure or intolerance to other AADs were enrolled if they were willing to in-office insertion of implantable loop recorders or already implanted with pacemakers or defibrillators capable of remote monitoring. Exclusion criteria were known medical contraindications of dofetilide and unable to provide consent. After making a shared management decision, dofetilide was initiated in a physician office, and rhythm and QTc intervals were monitored by ECGs and CIEDs. Patients were followed to assess the efficacy and safety of the treatment. Results: The study cohort comprised of 30 patients, age 76 ± 7 years (mean ± standard deviation), 10 female (33%), CHA2DS2-VASc score 3.25 ± 1.3, ejection fraction 63.45% ± 8.52, and QTc interval 431.68 ± 45.09 ms. From 22 (73%) patients in AF at presentation, SR was restored in 14 (64%) patients after 4 doses of dofetilide. At 46 ± 59 days of follow-up, maintenance of SR in total 22 (73%) patients without cardiac adverse effects was accomplished. Conclusion: Effective and safe outpatient initiation of dofetilide during the extenuating circumstance of COVID-19 lockdown was possible in patients with AF who had CIEDs. [ABSTRACT FROM AUTHOR]

Dofetilide, a class III antiarrhythmic, is widely used in the treatment of cardiac arrhythmias. Antiarrhythmic drugs can have a long duration of action that prolongs the QT interval. This causes bradycardia that predisposes to R-on-T phenomenon subsequently leading to torsades de pointes (TdP). This necessitates constant monitoring to prevent or treat ventricular arrhythmias or bradycardia associated with cardiac medications. Although extremely rare, dofetilide overdose has been described in the literature. However, no evidence found in the current literature required prolonged intervention after the initial acute stabilization, leading to scarcity of data for treatment of ongoing dofetilide overdose. We present the case of an intentional dofetilide overdose in a 61-year-old Caucasian woman with a history of congestive heart failure, atrial fibrillation, stage IIIb chronic kidney disease, diabetes mellitus type II, hypothyroidism, morbid obesity, and hypertension that required extensive interventions for refractory TdP that lasted 4 days. Therapeutic as well as excess dosage of dofetilide can lead to TdP, which is usually controlled by decreasing the dose or terminating drug administration. If the arrhythmia is not resolved, guidelines recommend management with activated charcoal if ingestion is within 15 minutes, followed by administration of 2 g IV (intravenous) magnesium and addressing the electrolyte imbalance. However, if the arrhythmia is persistent due to ongoing dofetilide toxicity, isoproterenol is given as a bridge to overdrive pacing and dopamine is used as an alternative to isoproterenol. [ABSTRACT FROM AUTHOR]

Pharmacological cardioversion using intravenous antiarrhythmic agents is commonly indicated in symptomatic patients with recent‐onset atrial fibrillation (AF). Except in hemodynamically unstable patients who require emergency direct current electrical cardioversion, for the majority of hemodynamically stable patients, pharmacological cardioversion represents a valid option and requires the clinician to be familiar with the properties and use of antiarrhythmic agents. The main characteristics of selected intravenous antiarrhythmic agents for conversion of recent‐onset AF, the reported success rates, and possible adverse events are discussed. Among intravenous antiarrhythmics, flecainide, propafenone, amiodarone, sotalol, dofetilide, ibutilide, and vernakalant are commonly used. Antazoline, an old antihistaminic agent with antiarrhythmic properties was also reported to give encouraging results in Poland. Intravenous flecainide and propafenone are the only Class I agents still recommended by recent guidelines. Intravenous new Class III agents as dofetilide and ibutilide have high and rapid efficacy in converting AF to sinus rhythm but require strict surveillance with electrocardiogram (ECG) monitoring during and after intravenous administration because of the potential risk of QT prolongation and Torsades de Pointes, which can be prevented and properly managed. Vernakalant, a partial atrial selective was shown to have a high success rate and to be safe in real‐life use. [ABSTRACT FROM AUTHOR]

Background: Atrial fibrillation is the most prevalent cardiac arrhythmia, presenting symptomatic patients with diminished quality of life and worsening of heart failure. Dofetilide, a class 3 antiarrhythmic agent, is a proven and safe rhythm control medication. Initial risk of QT prolongation leading to torsade de pointes (TdP) necessitates a standard protocol mandating hospitalization for three days for initiation., Objectives: To assess safety when adhering to initiation protocol and identify traits for susceptibility to TdP in elective dofetilide admissions., Methods: We conducted a retrospective study involving patients admitted to Mayo Clinic sites across four states for elective inpatient initiation of dofetilide between 2003 and 2022. Patients' charts underwent review, focusing on dofetilide-related TdP occurrences, baseline characteristics including QT intervals, laboratory values, comorbidities, and concomitant medications. Patients who experienced TdP were subjected to further evaluation to identify potential risk factors., Results: Of 2036 patients identified, mean age 66.4 ± 11.4 years, and 67.2 % male, 16 experienced dofetilide-related TdP (incidence rate 0.79%). Notably, 81% (13/16) of TdP cases occurred in patients who deviated from the FDA/manufacturer algorithm protocol. The concomitant use of active intravenous diuretic therapy, digoxin, and QT-prolonging drugs emerged as identifiable risk factors. Additionally, females exhibited a higher incidence of TdP (1.5%) than males (0.44%) {odd ratio [OR] 3.46; P = 0.017}., Conclusion: Overall incidence of TdP related to dofetilide initiation was low (0.79%). Adherence to protocol during elective hospital admissions appears extraordinarily safe. Patients who did not require concurrent use of intravenous diuretics, digoxin, or QT prolonging drugs exhibited lower risk of TdP., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)

Byline: Sudip. Nanda, Vikas. Yellapu, Matthew. Krinock Sir, Colchicine is an anti-mitotic, anti-inflammatory drug that prevents microtubule formation, actively degrades microtubules, and affects inflammatory mediators like interleukin-8/interleukin-18.[1],[2] It is used [...]

The aim of this article is to describe the pharmacist-managed dofetilide initiation program at Maine Medical Center (MMC), assess the adherence rate to 8 core clinical metrics, and review adverse effects before and after a root cause analysis (RCA). Core clinical metrics included pharmacist note entered within 4 hours of dose administration, dose chosen correctly per renal function, QTc measurements obtained and reviewed 2 hours after each dose, appropriate dose adjustment per the most recent QTc measurement, documentation of patient education, and assessment of conduction abnormality, drug–drug interactions, and serum potassium and magnesium concentrations. The primary outcome was adherence rate to all 8 core clinical metrics before and after the RCA. The safety outcome was the total number of adverse events. One hundred patients undergoing elective dofetilide initiation were evaluated: 50 pre-RCA and 50 post-RCA. Adherence rate to all core metrics was 14% in the pre-RCA group and 44% in the post-RCA group (P <.001). Torsade de pointes occurred 3 times in the pre-RCA group and never in the post-RCA group. After the RCA, adherence to MMC's pharmacist-managed inpatient dofetilide initiation program significantly improved. [ABSTRACT FROM AUTHOR]

Human-ether-a-go-go-related channel (hERG1) is the pore-forming domain of the delayed rectifier K+ channel in the heart which underlies the IKr current. The channel has been extensively studied due to its propensity to bind chemically diverse group of drugs. The subsequent hERG1 block can lead to a prolongation of the QT interval potentially leading to an abnormal cardiac electrical activity. The recently solved cryo-EM structure featured a striking non-swapped topology of the Voltage-Sensor Domain (VSD) which is packed against the pore-domain as well as a small and hydrophobic intra-cavity space. The small size and hydrophobicity of the cavity was unexpected and challenges the already-established hypothesis of drugs binding to the wide cavity. Recently, we showed that an amphipathic drug, ivabradine, may favorably bind the channel from the lipid-facing surface and we discovered a mutant (M651T) on the lipid facing domain between the VSD and the PD which inhibited the blocking capacity of the drug. Using multi-microseconds Molecular Dynamics (MD) simulations of wild-type and M651T mutant hERG1, we suggested the block of the channel through the lipid mediated pathway, the opening of which is facilitated by the flexible phenylalanine ring (F656). In this study, we characterize the dynamic interaction of the methionine-aromatic cassette in the S5-S6 helices by combining data from electrophysiological experiments with MD simulations and molecular docking to elucidate the complex allosteric coupling between drug binding to lipid-facing and intra-cavity sites and aromatic cassette dynamics. We investigated two well-established hERG1 blockers (ivabradine and dofetilide) for M651 sensitivity through electrophysiology and mutagenesis techniques. Our electrophysiology data reveal insensitivity of dofetilide to the mutations at site M651 on the lipid facing side of the channel, mirroring our results obtained from docking experiments. Moreover, we show that the dofetilide-induced block of hERG1 occurs through the intracellular space, whereas little to no block of ivabradine is observed during the intracellular application of the drug. The dynamic conformational rearrangement of the F656 appears to regulate the translocation of ivabradine into the central cavity. M651T mutation appears to disrupt this entry pathway by altering the molecular conformation of F656.