Clinical efficacy of dofetilide for the treatment of atrial tachyarrhythmias in adults with congenital heart disease.

BACKGROUND: Atrial tachyarrhythmias (AT) including atrial fibrillation (AF), atrial flutter (AFL), and atrial tachycardia represent a clinical challenge in the adult with congenital heart disease (CHD). Dofetilide (D) is a rapidly activating delayed rectifier potassium channel (IKr) blocker effective in pharmacological conversion and maintenance of normal sinus rhythm in patients with AF and AFL. There is limited knowledge regarding the role of D in adults with CHD. METHODS: Safety and efficacy of D was evaluated in a consecutive group of thirteen adult patients (age 40 ± 11; six women) with CHD and refractory AT. RESULTS: Ten patients had persistent (four AFL, one AF, and five atrial tachycardia) and three paroxysmal (one AF and two atrial tachycardia) AT. All patients were symptomatic during tachycardia, 12 patients had previously failed 2 ± 1 antiarrhythmic drugs. Mean systemic ventricular ejection fraction was 55 ± 9%; baseline QRS complex duration was 129 ± 45 ms (>120 ms in six patients). Patients were followed on D for 33 ± 39 months (median 16). Among 10 patients with persistent AT, seven patients (70%) pharmacologically converted to sinus rhythm on D and three patients (30%) required direct current cardioversion. Two patients (15.4%) experienced complete arrhythmia suppression, and seven (53.8%) experienced significant clinical improvement with sporadic recurrences; average time to recurrence was 5.5 ± 3.5 months. One patient developed torsade de pointes during loading, and the drug was discontinued. D was discontinued in five (38.5%) other patients due to recurrence of AT (n = 4) and renal failure (n = 1). Corrected QT interval (QTc) increased from 452 ± 61 to 480 ± 49 ms (P = .04) and corrected JT interval (JTc) from 323 ± 39 to 341 ± 33 ms (P = .09). CONCLUSIONS: D should be considered a pharmacologic alternative when adult patients with CHD develop AT. D does not depress conduction, sinus node, or ventricular function but needs close monitoring for potential ventricular pro-arrhythmia.

Clinical significance of increased tricuspid valve incompetence following implantation of ventricular leads.

PURPOSE: Cardiac rhythm management devices (CRMD) require a ventricular lead to be placed across the tricuspid valve. Tricuspid regurgitation (TR) is an under-recognized clinical complication of lead implantation and its clinical significance is unknown. We studied the incidence of hospitalizations for congestive heart failure (CHF) exacerbation among patients with worsening TR after ventricular lead implantation. METHODS: We reviewed 148 patients (age 68 ± 15) that received a CRMD. TR and pulmonary artery systolic pressure (PASP) measured by Doppler echocardiography before and after CRMD implantation were analyzed. Hospitalizations for CHF exacerbation post-implantation were counted. RESULTS: Follow-up was 32 ± 14 months. Ninety-nine (67%) patients had no change, 24 (16%) slight, and 9 (6%) significant increase in TR after CRMD implantation, while 13 (9%) patients had slight and 3 (2%) significant improvement. Patients with a significant increase in TR had higher incidence of hospitalizations (1.7 ± 0.5) compared to patients with slight (0.8 ± 1; p = 0.006) or no increase (0.5 ± 1; p = 0.0002) in TR. Patients with significant increase in TR had a greater change in PASP (25 mmHg; p = 0.002) after device implantation compared to those with a slight (10 mmHg; p = 0.002) or no increase (0.7 mmHg; p = 0.17). CONCLUSION: Increased TR following CRMD implantation is relatively common (33%) and correlated with subsequent risk of hospitalization for heart failure. A preventive strategy and close monitoring for development or worsening of CHF after CRMD implantation may help prevent hospital admissions.

Dofetilide reduces the frequency of ventricular arrhythmias and implantable cardioverter defibrillator therapies.

BACKGROUND: Patients with an implanted cardioverter defibrillator (ICD) and ventricular arrhythmias leading to ICD therapies have poor clinical outcomes and quality of life. Antiarrhythmic agents and catheter ablation are needed to control these arrhythmias. Dofetilide has only been approved for the treatment of atrial fibrillation. The role of dofetilide in the control of ventricular arrhythmias in patients with an ICD has not been established. OBJECTIVE: Evaluate the safety and efficacy of dofetilide in a consecutive group of patients with an ICD and recurrent ventricular tachycardia (VT) and/ or ventricular fibrillation (VF) after other antiarrhythmic drugs have failed to suppress these arrhythmias. METHODS: We studied 30 patients (age 59 ± 11; 5 women) with symptomatic VT or VF and ICDs for secondary prevention of sudden cardiac death. These patients had an average of 1.8 ± 4.5 episodes of VT/VF per month despite antiarrhymic therapy. Twenty-one patients (70%) had recurrent appropriate ICD therapies prior to initiation of dofetilide, and 9 (30%) VTs below the programmed detection rate of the ICD. Twenty-three patients (77%) had coronary artery disease. Mean ejection fraction was 30 ± 14% and 26/30 (87%) had congestive heart failure. All patients had previously failed 2 ± 1 antiarrhythmic drugs including amiodarone (n = 19) and sotalol (n = 10). RESULTS: During the first month of treatment, 25 patients (83%) had complete suppression of VT/VF and of the 21 patients with ICD therapies 16 (76%) had no therapies during the first month of treatment. During a follow-up period of 32 ± 32 months, dofetilide reduced the monthly episodes of VT/VF from 1.8 ± 4.5 to 1.0 ± 3.5 (P = 0.006). Monthly ICD therapies decreased from 0.9 ± 1.4 to 0.4 ± 1.7 (P = 0.037). In 9 patients that presented with slow VTs under the ICD detection zone, dofetilide reduced monthly VT/VF episodes from 0.7 ± 0.6 to 0.1 ± 0.1 (P = 0.01) and 6 (67%) had no further ICD therapies. Dofetilide was discontinued in 13 patients (43%) after 24 ± 30 months due to failure to control VT/VF (n = 7), placement of a left ventricular assist device (n = 3), catheter ablation (n = 1), heart transplantation (n = 1), and left ventricular restoration surgery (n = 1). There were 7 documented deaths (2 patients died suddenly; 3 patients of progressive heart failure; and 2 of non-cardiac causes). CONCLUSIONS: In patients with an ICD and ventricular arrhythmias, dofetilide decreases the frequency of VT/VF and ICD therapies even when other antiarrhythmic agents, including amiodarone, have previously been ineffective. Recurrences still occur in some patients requiring catheter ablation, mechanical support, or heart transplantation.

Safety and efficacy of dronedarone in the treatment of atrial fibrillation/flutter.

Dronedarone is an amiodarone analog but differs structurally from amiodarone in that the iodine moiety was removed and a methane-sulfonyl group was added. These modifications reduced thyroid and other end-organ adverse effects and makes dronedarone less lipophilic, shortening its half-life. Dronedarone has been shown to prevent atrial fibrillation/flutter (AF/AFl) recurrences in several multi-center trials. In addition to its rhythm control properties, dronedarone has rate control properties and slows the ventricular response during AF. Dronedarone is approved in Europe for rhythm and rate control indications. In patients with decompensated heart failure, dronedarone treatment increased mortality and cardiovascular hospitalizations. However, when dronedarone was used in elderly high risk AF/AFl patients excluding such high risk heart failure, cardiovascular hospitalizations were significantly reduced and the drug was approved in the USA for this indication in 2009 by the Food and Drug Administration. Updated guidelines suggest dronedarone as a front-line antiarrhythmic in many patients with AF/Fl but caution that the drug should not be used in patients with advanced heart failure. In addition, the recent results of the PALLAS trial suggest that dronedarone should not be used in the long-term treatment of patients with permanent AF.

Cardiac resynchronization therapy: evaluation of ventricular dysynchrony and patient selection.

Cardiac resynchronization therapy (CRT) is an established treatment modality for systolic heart failure. Aimed to produce simultaneous biventricular stimulation and correct the lack of ventricular synchrony in selected patients with congestive heart failure, CRT has shown to improve mortality and reduce hospital admissions when compared to medical treatment. At present, the indication criteria for the implantation of a CRT device include an ejection fraction of less than 35%, heart failure symptoms consistent with NYHA functional class III-IV and a QRS complex duration equal or longer than 120 milliseconds. It has been reported that 30% of patients who meet those criteria still may not derive clinical benefit from CRT. Due to the existing diversity of imagin modalities and resources for their process and analysis, a great expectation in terms of more accurate diagnosis of ventricular dyssynchrony has been raised. Reilable identification of dyssynchrony could allow us to better predict the favorable response of an individual patient to CRT and therefore offer this procedure to those individuals most likely to benefit. We review the available techniques for the study of ventricular dyssynchrony for CRT patient selection and the results of its application in clinical trials. Despite tremendous progress in the imaging technology available for the assessment and diagnosis of ventricular dyssynchrony, an ideal method has not been identified and the duration of QRS complex in the surface ECG remains the accepted criteria of dyssynchrony in the selection of patients for CRT.

Cardiac resynchronization therapy: evaluation of ventricular dysynchrony and patient selection / Terapia de resincronización cardiaca: evaluación de la disincronía ventricular y selección de pacientes

Cardiac resynchronization therapy (CRT) is an established treatment modality for systolic heart failure. Aimed to produce simultaneous biventricular stimulation and correct the lack of ventricular synchrony in selected patients with congestive heart failure, CRT has shown to improve mortality and reduce hospital admissions when compared to medical treatment. At present, the indication criteria for the implantation of a CRT device include an ejection fraction of less than 35%, heart failure symptoms consistent with NYHA functional class III-IV and a QRS complex duration equal or longer than 120 milliseconds. It has been reported that 30% of patients who meet those criteria still may not derive clinical benefit from CRT. Due to the existing diversity of imaging modalities and resources for their process and analysis, a great expectation in terms of more accurate diagnosis of ventricular dyssynchrony has been raised. Reliable identification of dyssynchrony could allow us to better predict the favorable response of an individual patient to CRT and therefore offer this procedure to those individuals most likely to benefit. We review the available techniques for the study of ventricular dyssynchrony for CRT patient selection and the results of its application in clinical trials. Despite tremendous progress in the imaging technology available for the assessment and diagnosis of ventricular dyssynchrony, an ideal method has not been identified and the duration of the QRS complex in the surface ECG remains the accepted criteria of dyssynchrony in the selection of patients for CRT.

La terapia de resincronización cardiaca es una modalidad de tratamiento bien establecida para la insuficiencia sistólica cardiaca. Dirigida a producir una estimulación biventricular simultánea y a corregir la falta de sincronía ventricular en pacientes seleccionados con insuficiencia cardiaca congestiva, la terapia de resincronización cardiaca ha mostrado ser capaz de mejorar los índices de mortalidad y reducir las admisiones hospitalarias cuando se compara con el tratamiento médico. Actualmente, los criterios para la implantación de un dispositivo de terapia de resincronización cardiaca incluyen una fracción de eyección menor a 35%, síntomas de insuficiencia cardiaca consistentes con la clase funcional NYHA III-IV, y una duración del complejo QRS igual o mayor de 120 milisegundos. Se ha reportado que 30% de los pacientes que cumplen con estos criterios pueden inclusive no obtener beneficio clínico de la terapia de resincronización cardiaca. Debido a la diversidad existente de los estudios de imagenología y de los recursos para su proceso y análisis, ha surgido una gran expectativa en términos de un diagnóstico más exacto de la asincronía ventricular. La identificación confiable de la asincronía nos podría permitir predecir mejor la respuesta favorable de un paciente en particular a la terapia de resincronización cardiaca y así ofrecer este procedimiento a aquellos pacientes con mayores probabilidades de beneficiarse de dicha terapia. Hacemos una revisión de las técnicas disponibles para el estudio de la asincronía ventricular para la selección de pacientes para esta terapia y los resultados de su aplicación en pruebas clínicas. A pesar de los grandes progresos alcanzados en la tecnología de imágenes disponibles para la evaluación y diagnóstico de la asincronía ventricular, no se ha identificado un método ideal y la duración del complejo QRS en el ECG de superficie sigue siendo el criterio aceptado de asincronía en la selección de pacientes para terapia de resincronización cardiaca.

A review of the appropriate and inappropriate use of dronedarone: lessons learned from controlled studies and regulatory submission.

Dronedarone is a multichannel blocker with electrophysiologic effects similar to amiodarone. Dronedarone has been documented to prevent atrial fibrillation recurrences and also has efficacy in slowing the ventricular response during episodes of atrial fibrillation. However, in the ANDROMEDA trial, dronedarone was associated with increased mortality when tested in New York Heart Association (NYHA) III/IV patients with left ventricular ejection fractions of less than 35%, who also had a recent hospitalization for decompensated heart failure. When such high-risk patients with heart failure were excluded in the ATHENA trial, dronedarone treatment resulted in a statistical reduction in the composite primary end point of all-cause mortality or cardiovascular hospitalization. In ATHENA, dronedarone reduced cardiovascular hospitalizations even though in the DIONY-SOS trial dronedarone had less effect than amiodarone on suppressing atrial fibrillation recurrences. The most appropriate patients for treatment with dronedarone would be patients with a recent history of paroxysmal or persistent atrial fibrillation/atrial flutter (AF/AFL) that have associated risk factors per the inclusion criteria of ATHENA. Inappropriate patients would be those with class IV heart failure or recently hospitalized for heart failure within the last month from an acute decompensation, the main inclusion criteria in ANDROMEDA. Dronedarone is a novel, multichannel blocking antiarrhythmic agent that may have some pleiotropic effects in addition to its ability to suppress and maintain sinus rhythm and control the rate during AF/AFL recurrences.

Dronedarone for the treatment of atrial fibrillation and atrial flutter: approval and efficacy.

Dronedarone, a new Class III antiarrhythmic agent, has now been approved by the US Food and Drug Administration for use in patients with atrial fibrillation or atrial flutter. Approval came in March 2009 due to the positive results of the ATHENA trial showing significant reductions in all-cause mortality and cardiovascular hospitalization with dronedarone use. A post hoc analysis of the ATHENA data also suggested a decrease in stroke risk with this agent. However, due to safety concerns in the heart failure population in the earlier ANDROMEDA trial, dronedarone is not recommended for patients with an ejection fraction <35% and recent decompensated heart failure. Dronedarone is an amiodarone analog with multichannel blocking electrophysiologic properties similar to those of amiodarone, but several structural differences. Dronedarone's lack of the iodine moiety reduces its potential for thyroid and pulmonary toxicity. Preliminary data from the DIONYSOS trial, and an indirect meta-analysis comparing amiodarone with dronedarone, showed amiodarone to be more effective in maintaining sinus rhythm, while dronedarone was associated with fewer adverse effects resulting in early termination of the drug. Dronedarone is the first antiarrhythmic drug for the treatment of atrial fibrillation and atrial flutter shown to reduce cardiovascular hospitalizations. In patients with structural heart disease who have an ejection fraction >35% and no recent decompensated heart failure, dronedarone should be considered earlier than amiodarone in the treatment algorithm.

Distal balloon occlusion allows epicardial lead placement in a tortuous branch of the great cardiac vein.

Cardiac resynchronization therapy (CRT) is a well established treatment modality in heart failure. Using standard techniques, placement of the left ventricular (LV) lead is usually successful; however LV lead placement failure remains a clinical problem. In the present report, the standard over-the-wire technique was not successful due to absence of the necessary support to place the lead into a tortuous vein. This was achieved using balloon occlusion of the great cardiac vein distal to the target vessel. An 81 year old female candidate for CRT presented for biventricular pacemaker implantation. After placement of the right ventricular lead, the CS was cannulated and an occlusive venogram was performed. A lateral branch was selected as the target vessel. Initial attempts at cannulating the vessel were unsuccessful due to the guidewire and telescoping delivery system prolapsing into the great cardiac vein. The acute angle prevented instrumentation of the branch with the tools available. A second parallel CS sheath was advanced to drive a balloon catheter used to occlude the great cardiac vein distal to the target vessel. This provided support for the guidewire and lead allowing their advancement through the tortuous vessel. Consecutive traction on the balloon during also helped to reflect the lead towards the vessel. The lead remained stable in its final position on the lateral wall of the LV with appropriate thresholds and no diaphragmatic stimulation. We report a case where balloon occlusion of the great cardiac vein distal to the target branch aided in advancing the LV lead into the desired position. This approach can be used in navigating lead placement to branches thought to be unreachable. Techniques such as this can decrease the failure rate of CRT implants.

Efficacy and safety of dofetilide in patients with atrial fibrillation and atrial flutter.

BACKGROUND: Dofetilide, an I(Kr) blocker has been demonstrated to be effective in terminating persistent atrial fibrillation and flutter (AF/AFL), and in maintaining sinus rhythm after direct current cardioversion (CV). It is not known, however, whether pharmacological conversion with dofetilide predicts maintenance of sinus rhythm. In addition, there is limited information comparing the efficacy of dofetilide in persistent versus paroxysmal AF/AFL. METHODS AND RESULTS: Eighty consecutive patients with AF/AFL (51 persistent, 29 paroxysmal) admitted for initiation of dofetilide were studied. Termination of persistent AF/AFL occurred in 61% of patients while 39% required CV. After 21 +/- 19 months of follow-up, 37% of patients with persistent AF/AFL were free of recurrence. Acute conversion with dofetilide did not predict long term efficacy. Dofetilide was more effective in maintaining sinus rhythm in patients with AFL (65%) than in those with AF (25%) (p < 0.05). Dofetilide was more likely to maintain sinus rhythm in patients with persistent than paroxysmal AF/AFL (37 vs. 14%; p < 0.05). Torsades de Pointes developed in two patients despite careful dosing and monitoring of QT changes. CONCLUSIONS: Dofetilide is more effective in patients with persistent than in those with paroxysmal AF/AFL. Importantly, short-term response does not necessarily predict long-term efficacy. Significant proarrhythmia can occur even with careful in-hospital monitoring.

Vernakalant: pharmacology electrophysiology, safety and efficacy.

The development of new antiarrhythmic agents for the treatment of atrial fibrillation is advancing simultaneously on several fronts. The molecular structure of existing agents such as amiodarone is being modified in an attempt to improve safety and reduce adverse effects. Similarly, atrial-selective antiarrhythmic drugs are being developed to minimize the occurrence of ventricular proarrhythmia. One of these atrial-selective compounds is vernakalant, which has demonstrated efficacy in terminating atrial fibrillation when given intravenously. In addition, preliminary data suggest that it could also suppress recurrences when used orally. This paper reviews the pharmacology, electrophysiology, efficacy and safety of intravenous and oral vernakalant.

Vernakalant--a promising therapy for conversion of recent-onset atrial fibrillation.

BACKGROUND: This paper reviews the pharmacology, electrophysiology, efficacy and safety of intravenous and oral vernakalant hydrochloride (RSD-1235), a novel antiarrhythmic drug that has relative atrial selectivity by blocking potassium channels that are present in the atria and not the ventricle. In addition, this drug has important rate-dependent sodium channel blocking properties. METHODS: Currently, there few commercially approved intravenous antiarrhythmic agents for the conversion of atrial fibrillation. Intravenously, vernakalant has been demonstrated to be useful in terminating over 50% of recent-onset atrial fibrillation (< 7 days duration) with minimal ventricular proarrhythmic effects. Intravenous vernakalant is not effective in terminating atrial flutter. Oral vernakalant is currently undergoing study and appears to be effective in suppressing atrial fibrillation recurrences after cardioversion of persistent atrial fibrillation. RESULTS/CONCLUSION: Intravenous vernakalant has the potential to be an important agent in the conversion of atrial fibrillation and oral vernakalant may be a useful drug for the suppression of atrial fibrillation recurrences.

New antiarrhythmic treatment of atrial fibrillation.

Antiarrhythmic pharmaceutical development for the treatment of atrial fibrillation (AF) is moving in several directions. The efficacy of existing drugs, such as carvedilol, for rate control and, possibly, suppression of AF, is more appreciated. Efforts are being made to modify existing agents, such as amiodarone, in an attempt to ameliorate safety and adverse effect concerns. This has resulted in promising data from the deiodinated amiodarone analog, dronedarone, and further work with celivarone and ATI-2042. In an attempt to minimize ventricular proarrhythmia, atrial selective drugs, such as intravenous vernakalant, have demonstrated efficacy in terminating AF in addition to promising data in suppression recurrences when used orally. Several other atrial selective drugs are being developed by multiple manufacturers. Other novel therapeutic mechanisms, such as drugs that enhance GAP junction conduction, are being developed to achieve more effective drug therapy than is offered by existing compounds. Finally, nonantiarrhythmic drugs, such as angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, high-mobility group coenzyme A enzyme inhibitors and omega-3 fatty acids/fish oil, appear to have a role in suppressing AF in certain patient subtypes. Future studies will clarify the role of these drugs in treating AF.