Dofetilide is a class III antiarrhythmic agent approved for the maintenance of sinus rhythm in patients with persistent atrial fibrillation (AF). The goal of this study was to determine if chemical cardioversion (CCV) suggests a greater sensitivity to dofetilide and, therefore, portends a higher risk of proarrhythmia. We analyzed 99 consecutive patients with persistent AF who were loaded on dofetilide before cardioversion. CCV occurred after 2 ± 1.5 doses of dofetilide in 46 patients whereas electrical cardioversion (ECV) was required in the remaining 53 patients after 4.7 ± 1.3 doses. During index hospitalization, there were higher rates of dofetilide discontinuation because of QT prolongation or torsades de pointes (TdP) in the CCV group compared with the ECV group (24% vs 2%, p = 0.001). All patients with CCV requiring drug discontinuation converted after a single dose of dofetilide. Additionally, all 3 patients with TdP were in the CCV group. Furthermore, 15 of the 21 patients with CCV (71%) who converted after the first dose of dofetilide developed significant QT prolongation, requiring dose adjustment or discontinuation of drug. Among patients discharged on drug, AF recurrence and drug discontinuation rates were similar between groups at 2-year follow-up. In patients hospitalized for initiation of dofetilide, CCV occurs in almost 50% and is associated with higher rates of pathologic QT prolongation and TdP compared with those who require ECV. Once discharged on dofetilide, safety and efficacy is similar in both groups. In conclusion, patients with CCV may require closer monitoring for proarrhythmia.
Dofetilide is a class III antiarrhythmic agent approved for clinical use in 1999 for the maintenance of sinus rhythm in patients with highly symptomatic persistent atrial fibrillation (AF). Dofetilide is also indicated for chemical conversion of AF and atrial flutter to sinus rhythm. Although dofetilide has demonstrated both safety and efficacy in the long-term treatment of atrial arrhythmias, including patients with coronary artery disease and left ventricular dysfunction, its associated initial risk of QT prolongation and possible torsades de pointes (TdP) have mandated in-hospital initiation in all patient populations. Initiation of dofetilide is associated with chemical conversion (CCV) in 6% to 60% of patients, with the remainder requiring electrical cardioversion (ECV) once the agent has been loaded. During in-hospital dofetilide initiation, some patients will develop repolarization abnormalities or arrhythmias requiring dose adjustment or discontinuation. A limited number of studies have evaluated patient characteristics associated with proarrhythmic effects of dofetilide. In particular, the impact of CCV on outcome with dofetilide use has not been evaluated. The goal of this study was to determine patient characteristics associated with CCV and proarrhythmia in a cohort of patients initiated on dofetilide for the treatment of persistent AF.
Methods
This study was a retrospective cohort study that included 99 consecutive patients with symptomatic persistent AF and/or atrial flutter who were loaded with dofetilide before cardioversion from February 2003 to December 2009 at the University of Pittsburgh Medical Center. After Institutional Review Board approval for this project, each patient’s hospitalization and follow-up records were reviewed and data were compiled for analysis.
Patients were defined as having persistent AF on the basis of multiple serial electrocardiograms demonstrating AF before cardioversion and/or the description of the treating electrophysiologist as stating that the patient has been in AF for >1 week unless cardioversion was attempted. Patients were included only if their electrocardiogram at the time of index hospitalization showed AF.
Before initiation of dofetilide, all patients were appropriately anticoagulated, and agents contraindicated in the presence of dofetilide were discontinued. All patients were monitored with continuous telemetry. Complete 12-lead electrocardiograms (ECGs) were obtained 2 hours after each dofetilide dose for a total of 6 doses. Initial dosing and dose adjustments were made on the basis of manufacturer recommended protocol. QT prolongation requiring drug discontinuation or any TdP was considered a toxicity of dofetilide.
Once the clinical characteristics of the cohort were established, the study population was then divided into 2 groups according to the type of cardioversion. The 2 groups were compared using the chi-square test for categorical variables and the student t test for continuous variables. Kaplan-Meier estimates were performed of the specific patient groups as detailed in the Results section. Analysis was performed using SPSS statistics software (Version 19, IBM, 2010, Armonk, New York). p Values ≤0.05 were considered to be statistically significant.
Results
Of the 99 patients who met inclusion criteria for the study, CCV occurred after 2.2 ± 1.5 doses of dofetilide in 46 patients, whereas ECV was required in the remaining 53 patients. ECV was performed at the discretion of the treating electrophysiologist after 4.7 ± 1.3 doses. Baseline characteristics in the 2 groups did not differ significantly ( Table 1 ).
| Variable | All Patients (n = 99) | CCV (n = 46) | ECV (n = 53) | p |
|---|---|---|---|---|
| Age (yrs) | 60 ± 11 | 61 ± 11 | 59 ± 11 | 0.91 |
| Men | 73% | 72% | 76% | 0.62 |
| Coronary artery disease | 21% | 15% | 28% | 0.11 |
| Hypertension | 55% | 52% | 59% | 0.53 |
| Diabetes mellitus | 18% | 22% | 15% | 0.39 |
| Hyperlipidemia | 48% | 57% | 42% | 0.14 |
| Previous antiarrhythmic drug | 44% | 44% | 46% | 0.80 |
| Creatinine (mg/dl) | 1.0 ± 0.2 | 1.0 ± 0.2 | 0.9 ± 0.2 | 0.96 |
| Left atrial dimension (cm) | 4.8 ± 0.8 | 4.6 ± 0.7 | 5.0 ± 0.8 | 0.45 |
| Left ventricular ejection fraction (%) | 48 ± 14 | 48 ± 12 | 47 ± 16 | 0.11 |
| Number of doses before cardioversion | 3.4 ± 1.9 | 2.2 ± 1.5 | 4.7 ± 1.3 | 0.55 |
| Duration of atrial fibrillation (d) | 71 ± 92 | 75 ± 111 | 67 ± 68 | 0.26 |
Forty-six percent of patients in our cohort experienced CCV. A large percentage of patients who chemically converted with initiation of dofetilide did so after the first dose of drug (21 of 46, 46%). The number of patients who chemically converted on dofetilide decreased steadily with each subsequent dose of drug. Furthermore, patients who converted to sinus rhythm after a single dose of dofetilide had a much greater likelihood of toxicity than those who converted with subsequent doses. In fact, all of the 8 patients in the CCV group in whom dofetilide was discontinued because of toxicity had converted after their first dose. Five of those patients had pathologic QT prolongation and 3 developed TdP (2 with sustained TdP and 1 with nonsustained TdP). In all, 15 of the 21 CCV patients who converted after a single dose of dofetilide (71%) developed QT prolongation requiring dose adjustment or discontinuation of drug (See Figure 1 ). Twenty-eight patients required a dose decrease and 6 of those resulted in discontinuation due to prolonged QT interval (5 in CCV group and 1 in ECV group).
The 3 TdP patients had an average baseline QRS duration of 113 ms compared with 101 ms in the remainder of patients (p = 0.02) and a baseline corrected QT interval of 449 ms as opposed to 445 ms in the rest of the patient population (p = 0.2). All 3 patients experienced CCV after a single dose of dofetilide but did not develop TdP until 2 to 3 doses of medication. Two of the 3 patients who developed TdP were women; however, there were no statistically significant differences found between this small group and the remainder of the patient cohort.
Compared with the CCV group, only 1 patient in the ECV group developed QT prolongation that was significant enough to require discontinuation of dofetilide (17% vs 2%, p = 0.007). None of the patients in the ECV group were noted to develop pathologic arrhythmias during index hospitalization. Dose adjustment was required in 20 of 53 (38%) ECV patients compared with 20 of 46 (44%) in the CCV group (p = 0.56). Drug discontinuation for inefficacy in maintaining sinus rhythm during index hospitalization was the primary reason for drug discontinuation in the ECV group and did not occur in any CCV patients (15% vs 0%, p = 0.01).
ECGs were reviewed on all patients. Review of initial ECGs demonstrated atrial flutter in 5% whereas the remaining 95% had AF. Among all patients included in the study, mean heart rate was 88 beats/min, QRS duration 102 ms, QT interval 373 ms, and corrected QT interval (QTc) of 445 ms. Electrocardiograms performed after the final dose of dofetilide, either the sixth loading dose or final dose before discontinuation, showed a mean heart rate of 68 beats/min, QRS duration 104 ms, QT interval 447 ms, and QTc of 471 ms. Comparison of the CCV and ECV groups showed longer QRS duration in the CCV group compared with the ECV group on both baseline and final ECGs (105 vs 99 ms, p = 0.008 and 108 vs 100 ms, p = 0.005). QTc but not absolute QT interval also trended higher in the CCV group, although these values did not reach statistical significance (453 vs 437 ms, p = 0.11). All other electrocardiographic measurements were similar between the groups. (See Table 2 ).
| Characteristic | All Patients | CCV | ECV | p |
|---|---|---|---|---|
| Baseline ECG | ||||
| Atrial flutter | 5% | 4 | 1 | 0.12 |
| Heart rate (beats/min) | 88 ± 26 | 86 ± 29 | 89 ± 22 | 0.45 |
| QRS duration (ms) | 102 ± 29 | 105 ± 35 | 99 ± 21 | 0.008 |
| QT interval (ms) | 373 ± 49 | 380 ± 52 | 367 ± 45 | 0.68 |
| Corrected QT (ms) | 444 ± 40 | 453 ± 45 | 437 ± 34 | 0.11 |
| Final ECG | ||||
| Heart rate (beats/min) | 68 ± 16 | 66 ± 14 | 70 ± 18 | 0.58 |
| QRS duration (ms) | 104 ± 28 | 108 ± 34 | 100 ± 20 | 0.005 |
| QT interval (ms) | 447 ± 55 | 465 ± 57 | 431 ± 54 | 0.34 |
| Corrected QT (ms) | 471 ± 45 | 481 ± 51 | 462 ± 38 | 0.12 |
| Change in QTc (ms) | 25 ± 46 | 28 ± 47 | 23 ± 45 | 0.66 |
Stay updated, free articles. Join our Telegram channel
Full access? Get Clinical Tree
