Antiarrhythmic Drugs For Atrial Fibrillation Research Articles

Anti-arrhythmic drugs in atrial fibrillation: tailor-made treatments.

During the last decades, many improvements have been made regarding the treatment of atrial fibrillation in terms of risk prevention, anti-coagulation strategies, and gain in quality of life. Among those, anti-arrhythmic drugs (AADs) have progressively fallen behind and overtaken by technological aspects as devices as procedures are now the standards of care for many patients. But is this it? Are AADs doomed to be relegated to an obscure and rarely read paragraph of the European recommendations? Or could they be still employed safely and effectively? In the present paper, we will discuss contemporary evidence in order to define where AADs still play a pivotal role, how should AADs be used, and whether a tailored approach can be the way to propose the right treatment to the right patient.

Safety of Pill-in-the-Pocket Class 1C Antiarrhythmic Drugs for Atrial Fibrillation.

Guidelines recommend that initial trial of a "pill-in-the-pocket" (PIP) Class 1C antiarrhythmic drug (AAD) for cardioversion of atrial fibrillation (AF) be performed in a monitored setting because of the potential for adverse reactions. This study sought to characterize real-world, contemporary use of the PIP approach, including the setting of initiation and incidence of adverse events. This retrospective cohort study included all patients at the Hospital of the University of Pennsylvania treated with a PIP approach for AF between 2007 and2020. A total of 273 patients (age 56 ± 13 years; 182 [67%] male; CHA2DS2VASc score 1.1 ± 1.2) took a first dose of PIP AAD. Flecainide was used in 151 (55%) and propafenone in 122 (45%). The first dose of PIP AAD was taken in a monitored setting in 167 (62%). Significant adverse events occurred in 7 patients (3%), 2 of whom had taken the doseinamonitored setting. Significant adverse events included unexplained syncope (1 of 7), symptomatic bradycardia/hypotension(4 of 7), and 1:1 atrial flutter (2 of 7). All occurred in patients taking 300mg of flecainide (n=4) or 600mg of propafenone (n=3). Electrical cardioversion was performed in 29 (11%) patients because of failure of the AAD to terminate AF. One patient required intravenous fluids and vasopressors for 2 hours because of persistent hypotension andbradycardia. Two patients required permanent pacemakers for bradycardia. The remaining patients required no intervention. Our data support the current recommendation to initiate PIP AAD in a monitored setting because ofrare significant adverse reactions that can require urgent intervention.

Emerging Antiarrhythmic Drugs for Atrial Fibrillation.

Atrial fibrillation (AF), the most common cardiac arrhythmia worldwide, is driven by complex mechanisms that differ between subgroups of patients. This complexity is apparent from the different forms in which AF presents itself (post-operative, paroxysmal and persistent), each with heterogeneous patterns and variable progression. Our current understanding of the mechanisms responsible for initiation, maintenance and progression of the different forms of AF has increased significantly in recent years. Nevertheless, antiarrhythmic drugs for the management of AF have not been developed based on the underlying arrhythmia mechanisms and none of the currently used drugs were specifically developed to target AF. With the increased knowledge on the mechanisms underlying different forms of AF, new opportunities for developing more effective and safer AF therapies are emerging. In this review, we provide an overview of potential novel antiarrhythmic approaches based on the underlying mechanisms of AF, focusing both on the development of novel antiarrhythmic agents and on the possibility of repurposing already marketed drugs. In addition, we discuss the opportunity of targeting some of the key players involved in the underlying AF mechanisms, such as ryanodine receptor type-2 (RyR2) channels and atrial-selective K+-currents (IK2P and ISK) for antiarrhythmic therapy. In addition, we highlight the opportunities for targeting components of inflammatory signaling (e.g., the NLRP3-inflammasome) and upstream mechanisms targeting fibroblast function to prevent structural remodeling and progression of AF. Finally, we critically appraise emerging antiarrhythmic drug principles and future directions for antiarrhythmic drug development, as well as their potential for improving AF management.

International cohort study on the effectiveness of dronedarone and other antiarrhythmic drugs for atrial fibrillation in real-world practice (EFFECT-AF)

AimsTo evaluate the effectiveness and safety of dronedarone compared with other commonly used antiarrhythmic drugs (AADs) for preventing atrial fibrillation (AF) recurrences.Methods and resultsAn international observational cohort study in Germany, Spain, Italy, and the USA enrolling patients with AF receiving AAD therapy. Patients with New York Heart Association (NYHA) Class IV heart failure were excluded. Participants were followed for up to 18 months, regardless of discontinuation or subsequent AAD switches. Atrial fibrillation recurrence was captured by hospitalization, emergency room visit, or electrocardiogram-based documentation of AF. Confounding bias was controlled for in the analysis of AF recurrence using multivariate models of 19 variables for adjustment. A total of 1009 participants [mean age 67.2 (10.8) years, male to female ratio 1.3] were recruited from 170 centres, 693 (69%) of which were from across Europe and the remaining 316 (31%) from the USA. At the time of enrolment, participants were taking dronedarone (51%) or other AADs (49%) [flecainide or propafenone (42%), sotalol (11%), and amiodarone (47%)]. No significant differences in the risk of first confirmed AF recurrence with dronedarone vs. other AADs [crude hazard ratio (HR) 1.10 (95% confidence interval 0.85–1.42); adjusted HR 1.16 (0.87–1.55)] were found, irrespective of whether univariate or multivariate models were used. Reported safety events were in accordance with the known safety profile of dronedarone.ConclusionIn this population of patients from either Europe or the USA receiving dronedarone or another AAD, the effectiveness of dronedarone was comparable to that observed for other AADs in preventing first AF recurrence.

Abstract 12131: Improved Knowledge and Confidence of Antiarrhythmic Drugs in Atrial Fibrillation via Online Educational Intervention

Background: Antiarrhythmic drugs (AAD) are currently used for the management of patients with arrhythmias. Despite randomized trial and real-world data many physicians remain hesitant to select an AAD in the daily-life routine. Purpose: To determine if an online continuing professional development intervention could improve knowledge and confidence of cardiologists and primary care physicians (PCPs) related to real-world data for AAD. Methods: Cardiologists and PCPs electively participated in a video-based, 2-faculty educational panel discussion on AAD management of arrhythmias, including real-world data. Educational effect was assessed using a repeated pair, pre-assessment/post-assessment study design and a chi-square test assessed differences from pre- to post-assessment. P -values < .05 are statistically significant. Cramer’s V assessed level of educational effect using the range of < 0.06 (modest), 0.06-0.15 (noticeable), 0.16-0.26 (considerable), and > 0.26 (extensive). Data were collected June 5, 2020 through July 20, 2020. Results: Overall significant improvements were seen after education for cardiologists (N = 367; P < .0001; V = .359) and PCPs (N = 760; P < .0001; V = .359). Pre-assessment, the average correct response rate was 32% for cardiologists and 29% for PCPs, while post-assessment average correct response rates increased to 68% and 61%, respectively. Significant improvements were observed in cardiologists’ and PCPs’ knowledge related to the effect of AAD on outcomes (Table). As a result of the education, 36% of cardiologists and 45% of PCPs had a measurable improvement in confidence regarding selection of appropriate antiarrhythmic therapy for patients with AF. Conclusion: The statistically significant improvements observed in this intervention demonstrate that participation in a video-based panel discussion improved the knowledge and confidence regarding real-world data for AAD regarding their effects on outcomes.

Computational modeling for antiarrhythmic drugs for atrial fibrillation according to the genotypes

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): This work was supported by a grant [HI19C0114] from the Ministry of Health and Welfare. Additionally, the work was funded by grants [NRF-2019R1C1C100907512], and [NRF-2020R1A2B01001695] from the Basic Science Research Program run by the National Research Foundation of Korea (NRF) under the Ministry of Science, ICT & Future Planning (MSIP). Background The efficacy of antiarrhythmic drugs (AAD) can vary in patients with atrial fibrillation (AF) and the PITX2 gene affects the responsiveness of AADs. We explored the virtual AAD (V-AAD) responses between wild-type and PITX2+/- deficient AF conditions by realistic in-silico AF modeling. Methods We tested the V-AADs in AF modeling integrated with patients’ 3D-computed tomography and 3D-electroanatomical mapping, acquired in 25 patients (68% male, 59.8 ± 9.8 years old, 32.0% paroxysmal type). The ion currents for the PITX2+/- deficiency and each AAD (amiodarone, sotalol, dronedarone, flecainide, and propafenone) were defined based on previous publications. Results We compared the wild-type and PITX2+/- deficiency in terms of the action potential duration (APD90), conduction velocity (CV), maximal slope of restitution (Smax), and wave-dynamic parameters, such as the dominant frequency (DF), phase singularities (PS), and AF termination rates according to the V-AADs. The PITX2+/- deficient model exhibited a shorter APD90 (p < 0.001), a lower Smax (p < 0.001), mean DF (p = 0.012), PS number (p < 0.001), and a longer AF cycle length (AFCL, p = 0.011). Five V-AADs changed the electrophysiology in a dose dependent manner. AAD-induced AFCL lengthening (p < 0.001) and reductions in the CV (p = 0.033), peak DF (p < 0.001) and PS number (p < 0.001) were more significant in PITX2+/- deficient than wild-type AF. PITX2+/- deficient AF was easier to terminate with class IC AADs than the wild-type AF (p = 0.018). Conclusions The computational modeling-guided AAD test was feasible for evaluating the efficacy of multiple AADs in patients with AF. AF wave-dynamics and electrophysiological characteristics are different among the PITX2 deficient and the wild-type genotype models. BaselineChanges after AADClass ICClass IIIWild-typePITX2+/-p-valueWild-typePITX2+/-p-valueWild-typePITX2+/-p-valueWild-typePITX2+/-p-valueAPD90, (ms)243.7 ± 33.8184.4 ± 15.5<0.00138.2 ± 37.343.4 ± 56.20.223275.9 ± 43.5219.0 ± 39.2<0.001284.9 ± 32.8233.8 ± 71.4<0.001CV, (m/s)0.78 ± 0.320.70 ± 0.210.347-0.15 ± 0.18-0.20 ± 0.260.0330.63 ± 0.320.53 ± 0.300.0270.60 ± 0.360.43 ± 0.33<0.001Mean Smax0.787 ± 0.280.531 ± 0.18<0.0010.005 ± 0.260.115 ± 0.24<0.0010.828 ± 0.310.694 ± 0.320.0030.768 ± 0.320.608 ± 0.27<0.001Mean AFCL, (ms)146.96 ± 24.61164.78 ± 22.730.01122.62 ± 24.5537.92 ± 32.72<0.001165.44 ± 36.96190.85 ± 35.61<0.001169.05 ± 25.26203.35 ± 34.78<0.001Peak DF, (Hz)10.68 ± 2.9711.82 ± 3.340.211-2.98 ± 4.94-5.46 ± 4.66<0.00110.01 ± 4.397.23 ± 4.20<0.0016.30 ± 4.325.80 ± 4.070.301Mean DF, (Hz)6.80 ± 0.886.22 ± 0.710.012-1.95 ± 2.44-2.20 ± 1.990.2065.75 ± 1.784.53 ± 2.00<0.0014.14 ± 2.393.69 ± 2.000.077PS Number, (N)101086 ± 9608814150 ± 24778<0.001-59322 ± 99288-7409 ± 27856<0.00150579 ± 6523611568 ± 21868<0.00132951 ± 558643524 ± 8302<0.001PS Life Span, (ms)109.36 ± 113.90102.24 ± 226.640.889-24.87 ± 72.06-41.38 ± 126.350.073103.36 ± 180.6868.05 ± 162.790.14871.91 ± 141.8655.99 ± 217.970.454Table. Effects of AADs in the Wild-type and PITX2+/- Deficiency groupAbstract Figure. Wild-type vs. PITX2+/- baseline model

Computational Modeling for Antiarrhythmic Drugs for Atrial Fibrillation According to Genotype.

Background: The efficacy of antiarrhythmic drugs (AAD) can vary in patients with atrial fibrillation (AF), and the PITX2 gene affects the responsiveness of AADs. We explored the virtual AAD (V-AAD) responses between wild-type and PITX2+/−-deficient AF conditions by realistic in silico AF modeling.Methods: We tested the V-AADs in AF modeling integrated with patients' 3D-computed tomography and 3D-electroanatomical mapping, acquired in 25 patients (68% male, 59.8 ± 9.8 years old, 32.0% paroxysmal type). The ion currents for the PITX2+/− deficiency and each AAD (amiodarone, sotalol, dronedarone, flecainide, and propafenone) were defined based on previous publications.Results: We compared the wild-type and PITX2+/− deficiency in terms of the action potential duration (APD90), conduction velocity (CV), maximal slope of restitution (Smax), and wave-dynamic parameters, such as the dominant frequency (DF), phase singularities (PS), and AF termination rates according to the V-AADs. The PITX2+/−-deficient model exhibited a shorter APD90 (p < 0.001), a lower Smax (p < 0.001), mean DF (p = 0.012), PS number (p < 0.001), and a longer AF cycle length (AFCL, p = 0.011). Five V-AADs changed the electrophysiology in a dose-dependent manner. AAD-induced AFCL lengthening (p < 0.001) and reductions in the CV (p = 0.033), peak DF (p < 0.001), and PS number (p < 0.001) were more significant in PITX2+/−-deficient than wild-type AF. PITX2+/−-deficient AF was easier to terminate with class IC AADs than the wild-type AF (p = 0.018).Conclusions: The computational modeling-guided AAD test was feasible for evaluating the efficacy of multiple AADs in patients with AF. AF wave-dynamic and electrophysiological characteristics are different among the PITX2-deficient and the wild-type genotype models.

Antiarrhythmic drugs for atrial fibrillation: lessons from the past and opportunities for the future.

Atrial fibrillation (AF) remains a highly prevalent and troublesome cardiac arrhythmia, associated with substantial morbidity and mortality. Restoration and maintenance of sinus rhythm (rhythm-control therapy) is an important element of AF management in symptomatic patients. Despite significant advances and increasing importance of catheter ablation, antiarrhythmic drugs (AADs) remain a cornerstone of rhythm-control therapy. During the past 50 years, experimental and clinical research has greatly increased our understanding of AADs. As part of the special issue on paradigm shifts in AF, this review summarizes important milestones in AAD research that have shaped their current role in AF management, including (i) awareness of the proarrhythmic potential of AADs; (ii) increasing understanding of the pleiotropic effects of AADs; (iii) the development of dronedarone; and (iv) the search for AF-specific AADs. Finally, we discuss short- and long-term opportunities for better AF management through advances in AAD therapy, including personalization of AAD therapy based on individual AF mechanisms.

Comparative efficacy and safety of wenxin granule combined with antiarrhythmic drugs for atrial fibrillation: A protocol for a systematic review and network meta-analysis.

Background:The combination of Chinese patent medicine Wenxin Granules (WXG) and antiarrhythmic drugs has been widely used in the treatment of atrial fibrillation (AF), but the results are controversial. This study will conduct a network meta-analysis (NMA) based on data from randomized controlled trials to evaluate the efficacy and safety of WXG combined with ADDs (amiodarone, metoprolol, propafenone, bisoprolol, or other antiarrhythmic drugs) in the treatment of AF, which will perform comparisons or rankings of efficacy among the currently available therapeutic schemes in order to provide evidence to determine the optimal threshold and treatment regimen to AF patients.Methods and analysis:A comprehensive systematic literature search will be conducted in Cochrane Library, PubMed, Web of Science, EMBASE, Chinese Biomedical Literature Database (SinoMed), Chinese National Knowledge Infrastructure (CNKI), and WanFang database for randomized controlled trials about the WXG with ADDs. The NMA will be conducted following the PRISMA-NMA guidelines. Statistical analyses will be conducted by using Stata software (version 14.0) and RevMan software (version 5.3).Results:The results of this NMA will provide a high-quality evidence for the efficacy of WXG combined with ADDs in the treatment of AF, and a ranking of the therapeutic classes will also be presented.Conclusion:The protocol will provide updated evidence for the application of WXG for AF.

Efficacy and safety of ShenSongYangXin Capsule combined with antiarrhythmic drugs for atrial fibrillation: A protocol for systematic review and network meta-analysis.

Shen-Song-Yang-Xin Capsule (SSYX), a Chinese patent medicine, combined with antiarrhythmic drugs (AADs) in the treatment of atrial fibrillation (AF) has been widely applied in clinical practice, but the results are controversial. This study aims to conduct a network meta-analysis (NMA) based on data from the randomized controlled trials (RCTs) to evaluate the efficacy and safety of SSYX combined with ADDs in the treatment of AF. A comprehensive systematic literature search will be conducted in Cochrane Library, PubMed, Web of Science, EMBASE, Chinese Biomedical Literature Database (SinoMed), Chinese National Knowledge Infrastructure (CNKI), and WanFang database for RCTs about SSYX combined with ADDs. The primary outcomes will be the frequency of AF attack and P-wave dispersion, and the secondary outcomes will be the symptom improvements, left atrial diameter, and adverse events. Statistical analyses will be conducted by using WinBUGS software (version 1.4.3), Stata software (version 14.0) and RevMan software (version 5.3). The results of this NMA will provide a high-quality evidence for the efficacy of SSYX combined with ADDs in the treatment of AF, and a ranking of the therapeutic classes will also be presented. The protocol will provide updated evidence for the application of SSYX for AF. INTERNATIONAL PLATFORM OF REGISTERED SYSTEMATIC REVIEW AND META-ANALYSIS PROTOCOLS (INPLASY) REGISTRATION NUMBER:: The protocol of this systematic review and meta-analysis was registered on the INPLASY website (https://inplasy.com/inplasy-2020-8-0075/) and INPLASY registration number is INPLASY202080075.

Class 1C antiarrhythmic drugs in atrial fibrillation and coronary artery disease.

BackgroundClass 1C antiarrhythmic drugs (AADs) are effective first‐line agents for atrial fibrillation (AF) treatment. However, these agents commonly are avoided in patients with known coronary artery disease (CAD), due to known increased risk in the postmyocardial infarction population. Whether 1C AADs are safe in patients with CAD but without clinical ischemia or infarct is unknown. Reduced coronary flow capacity (CFC) on positron emission tomography (PET) reliably identifies myocardial regions supplied by vessels with CAD causing flow limitation.ObjectiveTo assess whether treatment with 1C AADs increases mortality in patients without known CAD but with CFC indicating significantly reduced coronary blood flow.MethodsIn this pilot study, we compared patients with AF and left ventricular ejection fraction ≥50% who were treated with 1C AADs to age‐matched AF patients without 1C AAD treatment. No patient had clinically evident CAD (ie, reversible perfusion defect, known ≥70% epicardial lesion, percutaneous coronary intervention, coronary artery bypass grafting, or myocardial infarction). All patients had PET‐based quantification of stress myocardial blood flow and CFC. Death was assessed by clinical follow‐up and social security death index search.ResultsA total of 78 patients with 1C AAD exposure were matched to 78 controls. Over a mean follow‐up of 2.0 years, the groups had similar survival (P = .54). Among patients with CFC indicating the presence of occult CAD (ie, reduced CFC involving ≥50% of myocardium), 1C‐treated patients had survival similar to (P = .44) those not treated with 1C agents.ConclusionsIn a limited population of AF patients with preserved left ventricle function and PET‐CFC indicating occult CAD, treatment with 1C AADs appears not to increase mortality. A larger study would be required to confidently assess the safety of these drugs in this context.

The clinical outcomes of patients who developed typical atrial flutter on class 1C anti arrhythmic medications treated with hybrid approach.

IntroductionA common approach to patients, who developed atrial flutter secondary to treatment with class 1C anti‐arrhythmic drugs for atrial fibrillation (AF) (1C flutter), is a hybrid approach: ablation of the Cavo‐Tricuspid isthmus (CTI) and continuation 1C medical treatment to prevent recurrence of AF. We aim to explore the clinical outcome of patients treated in this approach. Methods and ResultsTwo hundred and four consecutive patients who underwent ablation for typical AFL at a tertiary medical center between 2010 and 2016 were enrolled and followed up. The clinical outcome of patient treated by the hybrid approach (treatment group; n = 67) was compared to patient without history of AF (control group; n = 137). The primary endpoint was time to occurrence of AF. Twenty‐eight (41.8%) patients in treatment group had AF occurrence in 1 year, including 9 (13.4%) patients who needed to escalate anti‐arrhythmic drug treatment to class III, and 11 (16.4%) patients who underwent AF ablation. In comparison, only 21 (15.3%) patients in control group had occurrence during the first year after ablation. The median time from ablations till AF occur was 106 ± 481 days in treatment group, and 403 ± 668 days in control group (P < .01).ConclusionsThere is a relatively high rate of AF recurrence in patients treated with the hybrid approach during the first year after CTI ablation. An alternative approach should be considered in this selected population.

Observational study of dronedarone in Taiwanese patients with atrial fibrillation

Currently, data on the real-world use of dronedarone, an antiarrhythmic drug for atrial fibrillation (AF), are contradictory and often based on patient populations comprised of Caucasians. We prospectively investigated the efficacy and safety of dronedarone and risk factors related to treatment outcomes in a real-world use setting. The prospective, observational, single-arm, multi-center study included a total of 824 Taiwanese patients with a diagnosis of paroxysmal or persistent AF and receiving dronedarone treatment. Risk factors analysis, efficacy, and safety of dronedarone were assessed with a follow-up of six months. Of the 824 patients enrolled (mean age, 75.3±7.2 years), 95.2% had at least one cardiovascular risk factor. An increase in the proportion of patients with sinus rhythm following treatment was seen (52.1% at baseline vs. 67.4% at 6 months). A decrease in the mean duration of AF episodes (388.4min vs. 62.3min) and an increase in total AFEQT (65.4±16.2 vs. 74.0±11.8) were also observed after 6 months of treatment. Females, those under the age of 75, and those with symptomatic AF had higher odds of treatment success. At 6 months, 10.5% of patients reported treatment-related AEs. However, only 0.2% of the AEs were both severe in nature and causally related to dronedarone. This six-month study showed dronedarone to be relatively safe and efficacious and to improve quality-of-life in Taiwanese patients with atrial fibrillation. Odds of treatment success were related to the patient's gender, age, and AF type.

P199Short- and long-term efficacy and safety of catheter ablation versus antiarrhythmic drugs for atrial fibrillation: a meta-analysis of randomized trials

P199Short- and long-term efficacy and safety of catheter ablation versus antiarrhythmic drugs for atrial fibrillation: a meta-analysis of randomized trials

Atrial-selective K+ channel blockers: potential antiarrhythmic drugs in atrial fibrillation?

In the wake of demographic change in Western countries, atrial fibrillation has reached an epidemiological scale, yet current strategies for drug treatment of the arrhythmia lack sufficient efficacy and safety. In search of novel medications, atrial-selective drugs that specifically target atrial over other cardiac functions have been developed. Here, I will address drugs acting on potassium (K+) channels that are either predominantly expressed in atria or possess electrophysiological properties distinct in atria from ventricles. These channels include the ultra-rapidly activating, delayed outward-rectifying Kv1.5 channel conducting IKur, the acetylcholine-activated inward-rectifying Kir3.1/Kir3.4 channel conducting IK,ACh, the Ca2+-activated K+ channels of small conductance (SK) conducting ISK, and the two-pore domain K+ (K2P) channels (tandem of P domains, weak inward-rectifying K+ channels (TWIK-1), TWIK-related acid-sensitive K+ channels (TASK-1 and TASK-3)) that are responsible for voltage-independent background currents ITWIK-1, ITASK-1, and ITASK-3. Direct drug effects on these channels are described and their putative value in treatment of atrial fibrillation is discussed. Although many potential drug targets have emerged in the process of unravelling details of the pathophysiological mechanisms responsible for atrial fibrillation, we do not know whether novel antiarrhythmic drugs will be more successful when modulating many targets or a single specific one. The answer to this riddle can only be solved in a clinical context.

Ranolazine reduces atrial fibrillatory wave frequency.

Antiarrhythmic medications for the treatment of atrial fibrillation (AF) have limited efficacy and rare but potentially life-threatening side effects. Ranolazine is an antianginal agent that may have antiarrhythmic activity in AF. Using the Duke Enterprise Data Unified Content Explorer database, we analysed a cohort of AF patients on ranolazine. Patients served as their own historic control. Electrocardiograms (ECGs) were analysed before and after ranolazine initiation to determine the effect of ranolazine on dominant frequency (DF), f-wave amplitude, and organizational index (OI). We identified 15 patients with ECGs in AF before and after ranolazine. Ranolazine was associated with lower DF by an average of 10% (5.10 ± 0.74 vs. 5.79 ± 0.96 Hz, P = 0.04) but not with changes in OI (0.47 ± 0.11 vs. 0.50 ± 0.12, P = 0.71) or amplitude (0.47 ± 0.43 vs. 0.41 ± 0.40 mV, P = 0.82). Ranolazine was also associated with lower DF in patients (n = 10) not on concomitant antiarrhythmic therapy (5.25 ± 0.78 vs. 6.03 ± 0.79 Hz, P = 0.04). Ranolazine is associated with lower AF DF but no change in OI or fibrillatory wave amplitude. Prospective trials are needed to evaluate ranolazine's potential as a novel antiarrhythmic drug for AF.

Novel Use of Ranolazine as an Antiarrhythmic Agent in Atrial Fibrillation.

To review the limitations of current antiarrhythmic drugs in atrial fibrillation (AF) and discuss the rationale and clinical trials supporting the use of ranolazine in AF. MEDLINE was searched from 1980 to September 2016 using the terms ranolazine, atrial fibrillation, coronary artery bypass grafting, and valve surgery. English-language studies and reviews assessing antiarrhythmic drugs, including ranolazine, were incorporated. The use of ranolazine monotherapy has been evaluated in 2 clinical trials. In the RAFFAELLO trial, higher doses of ranolazine showed a trend toward lower AF recurrence versus placebo ( P = 0.053), but further evidence is needed to support its use as a sole therapeutic agent. Ranolazine has shown utility in a limited number of studies as an adjunctive agent, which is critical for those in whom standard therapy is inadequate or the adverse event profile precludes optimized standard therapy. In the HARMONY trial, ranolazine 750 mg and dronedarone 225 mg twice daily reduced the AF burden by 59.1% from baseline ( P = 0.008 vs placebo). In a trial by Koskinas and colleagues, patients receiving ranolazine 1500 mg once and intravenous amiodarone had a higher conversion rate than those receiving amiodarone alone ( P = 0.024). There are also promising studies for the prevention and treatment of post-cardiothoracic surgery AF, which require further investigation. Ranolazine's pharmacological properties and available evidence suggest potential for its use in AF.

New antiarrhythmic drugs for atrial fibrillation

AbstractAtrial fibrillation is a complex arrhythmia that is difficult to treat with conventional antiarrhythmic agents. Novel pharmacological approaches are in progress focused on the development of agents with selective affinity to ion channels predominately involved in the atrium. In parallel, research efforts have been focused on the development of agents targeting to modification of those pathways and molecular mediators which are involved in the propagation and maintenance of atrial fibrillation (AF). In this review, we focus on the basic and clinical pharmacology of new and emerging antiarrhythmic drugs such as vernakalant, dronedarone, and ranolazine, whereas we briefly comment on the future directions of antiarrhythmic therapy in AF.Answer questions and earn CME: https://wileyhealthlearning.com/Activity2/4469486/Activity.aspx

Abstract 12122: Persistence With Antiarrhythmic Agents in Atrial Fibrillation: Insights From the Veterans Health Administration

Background: There is limited information on patterns of persistence with antiarrhythmic drugs (AADs) in atrial fibrillation (AF). Nonpersistence may represent failure of AADs or patient/physician choice, therefore, we characterized AAD persistence patterns following discharge in patients admitted to the hospital with AF. Methods: This retrospective cohort study of patients with AF, diagnosed on index AF admission in the Veterans Health Administration from 2001-2010 used national inpatient, outpatient, pharmacy claims, and vital status data to identify patients and characterize persistence. We identified prescriptions for all initial AAs dispensed after AF diagnosis. Patients were considered nonpersistent if they had &gt;30-day gap in filling a repeat AAD prescription. Results: Of 206,331 patients with AF, 43,262 (21%) received an AAD, age was 68.1±10.4 years, 98% were male, and CHA2DS2-VASc score was 2 (IQR: 1-3). Patients were followed for 2 years after their index AAD prescription. Among AAD-treated patients, most received amiodarone (68%). In the 2 years after their first AAD was dispensed, 43% discontinued their AAD. The lowest rates of nonpersistence were with dofetilide (29%) and sotalol (33%). Median time to nonpersistence was 143 days (IQR 90, 289). Of patients who were nonpersistent (&gt;30-day gap), 46% restarted the same AAD, 7% switched to a different AAD, 33% switched to a rate control strategy, and 14% stopped the AAD strategy completely. Conclusion: Among patients with AF, 4 in 10 patients are nonpersistent with their initial AAD. Nearly 50% of patients restart their same AAD after nonpersistence, suggesting intermittent medication use likely due to patient nonadherence. One-third of patients who had initiated a rhythm control strategy with an AAD switched to a rate control strategy, indicating possible AAD failure. Given the magnitude of nonpersistence, future studies on predictors and outcomes of nonpersistence with AAD in AF are needed.

Potassium Channel Blockade Enhances Atrial Fibrillation-Selective Antiarrhythmic Effects of Optimized State-Dependent Sodium Channel Blockade.

The development of effective and safe antiarrhythmic drugs for atrial fibrillation (AF) rhythm control is an unmet clinical need. Multichannel blockers are believed to have advantages over single-channel blockers for AF, but their development has been completely empirical to date. We tested the hypothesis that adding K(+)-channel blockade improves the atrium-selective electrophysiological profile and anti-AF effects of optimized Na(+)-channel blockers. Realistic cardiomyocyte-, tissue-, and state-dependent Na(+)-channel block mathematical models, optical mapping, and action potential recording were used to study the effect of Na(+)-current (INa) blockade with or without concomitant inhibition of the rapid or ultrarapid delayed-rectifier K(+) currents (IKr and IKur, respectively). In the mathematical model, maximal AF selectivity was obtained with an inactivated-state Na(+)-channel blocker. Combining optimized Na(+)-channel blocker with IKr block increased rate-dependent and atrium-selective peak INa reduction, increased AF selectivity, and more effectively terminated AF compared with optimized Na(+)-channel blocker alone. Combining optimized Na(+)-channel blocker with IKur block had similar effects but without IKr block-induced ventricular action potential prolongation. Consistent with the mathematical model, in coronary-perfused canine hearts, the addition of dofetilide (selective IKr blocker) to pilsicainide (selective INa blocker) produced enhanced atrium-selective effects on maximal phase 0 upstroke and conduction velocity. Furthermore, pilsicainide plus dofetilide had higher AF termination efficacy than pilsicainide alone. Pilsicainide alone had no statistically significant effect on AF inducibility, whereas pilsicainide plus dofetilide rendered AF noninducible. K(+)-channel block potentiates the AF-selective anti-AF effects obtainable with optimized Na(+)-channel blockade. Combining optimized Na(+)-channel block with blockade of atrial K(+) currents is a potentially valuable AF-selective antiarrhythmic drug strategy.