Dofetilide In Structural Heart Disease
Overview
Dofetilide, a class III antiarrhythmic drug, is approved for managing atrial fibrillation and atrial flutter, but it has also been used off-label to treat premature ventricular complexes (PVCs) and ventricular tachycardias (VTs). This study aimed to assess the efficacy and safety of dofetilide for ventricular arrhythmias (VAs).
In a retrospective cohort study involving 81 patients (59 men, average age 60 ± 14 years, LVEF 0.34 ± 0.16), dofetilide was initiated to manage PVCs (29 patients), VTs (42 patients), or both (10 patients). The primary goal was to achieve at least an 80% reduction in PVC burden, which was deemed a satisfactory response. The majority of patients (89%) had an implantable cardioverter-defibrillator (ICD), 62% had previously been treated with another antiarrhythmic, and 41% had undergone prior catheter ablation.
During the initiation phase, 12 patients (15%) discontinued dofetilide due to QT prolongation (8 patients) or inefficacy in controlling VAs (4 patients). Among the 32 patients with PVCs who successfully started the medication, the average PVC burden reduced from 20 ± 10% to 8 ± 8% after a median follow-up of 2.6 months (p < .001). However, only 34% (11 out of 32 patients) achieved the desired reduction of ≥80% in PVC burden. Over a follow-up period of 7 ± 1 years, 59% of the patients (41 out of 69) continued to experience VAs, receiving appropriate ICD therapies for monomorphic VTs (35 patients) and polymorphic VT/VF (6 patients), with a median onset of 8.0 months (IQR 2.6–33.2). Ultimately, 72% of patients (50 out of 69) discontinued dofetilide due to inefficacy or intolerance.
The composite outcome of VT/VF recurrence, heart transplantation, or death occurred in 50% of patients (6 out of 12) without dofetilide and 71% of patients (49 out of 69) on dofetilide, with event-free survival rates showing no significant difference between the two groups (log-rank p = .55).
In conclusion, while dofetilide was associated with a reduction in PVC burden, a significant suppression of these arrhythmias was observed in only a small portion of patients. Moreover, the drug was largely ineffective in controlling VTs for most individuals.
Introduction
Class III antiarrhythmic drugs like amiodarone and sotalol are commonly used to manage premature ventricular complexes (PVCs) and ventricular tachycardia (VT), either alone or in combination with catheter ablation. However, these agents may sometimes be ineffective or poorly tolerated in patients with ventricular arrhythmias (VAs). Although dofetilide is primarily indicated for atrial fibrillation and atrial flutter, it is another class III antiarrhythmic that has proven safe and effective, even for individuals with structural heart disease. Dofetilide works by selectively blocking the rapid component of the delayed rectifier potassium current (IKr), which leads to prolongation of the action potential and the refractory period.
While dofetilide is not traditionally used for treating VAs, it may offer an alternative for patients who have not responded well to, or could not tolerate, other class III antiarrhythmic agents. However, its effectiveness in suppressing VAs has not been thoroughly evaluated. The objective of this study was to assess the safety and efficacy of dofetilide in managing ventricular arrhythmias in patients with structural heart disease.
Method
The study analyzed 81 consecutive patients treated exclusively with dofetilide for ventricular arrhythmias (VAs) between 2009 and 2023. The cohort included 59 men and 22 women, with a mean age of 60 years (±14) and a left ventricular ejection fraction (LVEF) of 0.34 (±0.16). The population comprised 23 patients (28%) with ischemic cardiomyopathy, 54 patients (68%) with nonischemic cardiomyopathy (32 idiopathic dilated, 7 left ventricular non-compaction, 3 myocarditis, 3 congenital heart disease, 1 arrhythmogenic right ventricular dysplasia, 5 sarcoidosis, 2 chemotherapy-induced, and 1 peripartum), and 3 patients (4%) with mixed cardiomyopathy.
Of these patients, 72 (89%) had implantable cardioverter-defibrillators (ICDs) for primary (20) or secondary prevention (52), and 25 (35%) received cardiac resynchronization therapy. Prior ICD therapies were administered to 68%, including ICD discharges in 46 patients and anti-tachycardia pacing in 3. Before dofetilide, 50 patients (62%) had already tried other antiarrhythmic drugs (AADs), including amiodarone, which was discontinued in 31 patients due to adverse events such as pulmonary toxicity and thyroid issues. Sotalol was stopped in 23 patients primarily due to limited efficacy or adverse effects like fatigue and QT prolongation.
In cases without prior AAD use (31 patients), dofetilide was selected based on factors like younger age, comorbidities, or patient and provider preferences. Catheter ablation had been attempted in 41% of patients, primarily targeting premature ventricular contractions (PVCs) and ventricular tachycardia (VT).
Dofetilide therapy followed U.S. FDA guidelines, with doses adjusted based on kidney function and QTc monitoring. Dose reductions were made if the QTc interval increased, and treatment was discontinued in cases of further QT prolongation or polymorphic VAs. The study’s primary outcome was the time to the first VT or ventricular fibrillation (VF) event, including ICD therapy. The composite endpoint included VT/VF recurrence, heart transplantation, or death. PVC reduction of at least 80% was considered a successful response.
Patients were followed up closely through a dedicated AAD clinic every 3 months, with ongoing QTc, renal function, and electrolyte monitoring. In patients with ICDs, additional follow-up occurred via remote monitoring every 3-6 months.
Statistical Analysis
Continuous variables were presented as mean ± 1 standard deviation or, in the case of non-normally distributed data, as median and interquartile range (IQR). The Student’s t-test was used for comparisons of these variables. For sequential continuous data, the Wilcoxon signed-rank test was applied. Categorical variables were analyzed using the χ2 test, but when expected counts in a 2 × 2 contingency table were less than 5, Fisher’s exact test was employed. Kaplan–Meier analysis was utilized to evaluate event-free survival, with subgroup differences assessed by the log-rank test. To examine the relationship between dofetilide use, clinical characteristics, and the composite outcome (which included recurrence of VT/VF, heart transplantation, and death), Cox regression analysis was performed. Statistical significance was defined as a two-tailed p-value less than 0.05.
Result
In a study of 81 patients, dofetilide was used to manage premature ventricular contractions (PVCs) in 29 patients (36%), ventricular tachycardias (VTs) in 42 patients (52%), and both arrhythmias in 10 patients (12%). The initial dofetilide dose was 500 mcg in 63 patients (78%), 250 mcg in 15 patients (18%), and 125 mcg in 3 patients (4%). At baseline, 25 patients (31%) were in a paced rhythm, and 22 patients (27%) had a pre-existing ventricular conduction abnormality. Among those with normal conduction, the QRS width and QTc interval were 96 ± 14 ms and 438 ± 28 ms, respectively. These values were increased in patients with conduction abnormalities and paced rhythms.
During dofetilide loading, 27 patients (33%) required dose adjustments due to QT prolongation. Successful initiation was achieved in 69 patients (85%), with maintenance doses of 500 mcg in 28 patients (41%), 250 mcg in 32 patients (46%), and 125 mcg in 9 patients (13%). QTc intervals increased across all groups post-treatment, with statistically significant changes. However, dofetilide was discontinued in 12 patients (15%) due to QT prolongation, ICD therapies, or increased PVC burden.
Efficacy data revealed that 59% of patients experienced appropriate ICD therapies for monomorphic or polymorphic VT/VF during follow-up. Additionally, dofetilide successfully reduced PVC burden in 34% of patients treated for frequent PVCs. There was no significant change in left ventricular ejection fraction (LVEF) before and after dofetilide therapy.
Long-term, dofetilide was discontinued in 72% of patients, primarily due to recurrent arrhythmias, QT prolongation, or successful ablation. Of note, 32% of patients underwent catheter ablation following dofetilide initiation, with successful ablation in the majority of PVC cases. During a mean follow-up of seven years, 71% of patients on dofetilide experienced recurrent VT/VF, heart transplantation, or death. Event-free survival was comparable between those who could and could not tolerate dofetilide, and multivariable analysis identified diabetes mellitus as an independent predictor of poor outcomes. Dofetilide therapy was not independently associated with the composite outcome of VT/VF recurrence, heart transplantation, or death.
Conclusion
The study’s main findings indicate that while dofetilide was initially successful in treating ventricular arrhythmias (VAs) in approximately 85% of patients, it was discontinued in 70% during long-term follow-up due to either inefficacy or intolerance. Notably, only 34% of patients achieved a clinically significant reduction (≥80%) in premature ventricular contractions (PVCs), and freedom from ventricular tachycardia (VT) was seen in about 40%. However, dofetilide did not significantly reduce the need for device therapies for VAs.
These results align with those from Shantha et al., who also found that dofetilide had limited utility in suppressing VT and PVCs over a two-year follow-up. Compared to prior studies, this cohort had a higher rate of discontinuation due to polymorphic VT or QT prolongation (22% versus 12%), and six patients experienced polymorphic VT during follow-up. This suggests that a lower tolerance for QT prolongation during drug loading and continued QT monitoring is crucial, especially as renal function changes.
In terms of efficacy, approximately 50% of patients treated with dofetilide for VT were free from VT requiring ICD shocks during long-term follow-up. This is lower than the VT-free survival rates (>70%) reported in prior studies involving sotalol and amiodarone, suggesting dofetilide may be less effective than these agents. Furthermore, the efficacy of dofetilide in reducing PVCs was lower than that of prior trials, which showed a greater response with higher intravenous doses.
The study has several limitations, including its retrospective nature and the heterogeneity of the patient cohort, many of whom had failed prior antiarrhythmic treatments or catheter ablation. The study also lacked the power to assess efficacy in specific subgroups, and the results may not be applicable to regions where dofetilide is unavailable.
In conclusion, dofetilide demonstrated limited efficacy in treating VAs in patients with structural heart disease, particularly in those who had not responded to other antiarrhythmic therapies or catheter ablation. However, it may still be considered as a treatment option in specific cases where alternatives are unavailable. With careful monitoring, long-term use of dofetilide appears safe in this patient population.
