Dronedarone is a novel class III antiarrhythmic drug with moderate efficacy in preventing atrial arrhythmias. However, only few data from the real-world use of dronedarone with limited electrocardiographic monitoring are available. The investigators report the incidence, timing, and reasons for discontinuation of dronedarone; maintenance of sinus rhythm; and atrial arrhythmia recurrence patterns in 120 consecutive patients with atrial fibrillation (AF; n = 91) or non-isthmus-dependent atrial flutter (n = 29) treated with dronedarone (400 mg twice daily). Rhythm control was assessed with serial 7-day Holter electrocardiography after 4 weeks and after 6 to 9 months. After drug initiation, dronedarone was discontinued in 19 patients (16%) because of inefficacy (n = 7 [6%]) or adverse events (n = 12 [10%]). At 4 weeks, 44 patients (37%) had stopped taking dronedarone because of inefficacy (n = 27 [23%]) or adverse events (n = 17 [14%]). After 6 to 9 months, 25 patients (21%) had discontinued dronedarone because of clinical inefficacy (n = 16 [13%]) or adverse events (n = 9 [8%]). Overall, dronedarone was still used after 6 to 9 months in 32 patients (27%). Maintenance of sinus rhythm was achieved in 40 patients (33%) after 4 weeks and in 24 patients (20%) after 6 to 9 months. Reversal from persistent to paroxysmal arrhythmias was observed in 23 patients, (29%) whereas progression from paroxysmal to persistent arrhythmias occurred in 6 patients (15%). Conversion from AF to non-isthmus-dependent atrial flutter was noted in 10 patients (13%). In conclusion, dronedarone is associated with frequent adverse events and moderate antiarrhythmic efficacy requiring discontinuation in most patients within the first 9 months of use, and there is a prevalent reversal from persistent to paroxysmal but also from paroxysmal to persistent atrial arrhythmias and from AF to non-isthmus-dependent atrial flutter.
Dronedarone is a class III antiarrhythmic drug for the treatment of patients with atrial fibrillation (AF) and atrial flutter that became available in the United States in July 2009 and in Germany in January 2010. Promising data from A Trial With Dronedarone to Prevent Hospitalization or Death in Patients With Atrial Fibrillation (ATHENA) showed a significant reduction of the time to first cardiovascular hospitalization or death in patients with paroxysmal or persistent AF or atrial flutter receiving dronedarone but more adverse events in those with permanent AF. Dronedarone has demonstrated moderate efficacy in maintaining sinus rhythm, with less efficacy but also fewer adverse events than amiodarone. Currently, only few limited data from the real-world use of dronedarone are available, showing an AF recurrence rate of 66% and a discontinuation rate of 22% after 14 months. However, in that study, serial electrocardiographic monitoring was not performed during follow-up. Consequently, the true rate of AF recurrences as well as possible arrhythmia transitions could not be detected. Thus, in this study, we focused on dronedarone treatment in clinical routine use with respect to (1) incidence, timing, and reasons for discontinuation, (2) maintenance of sinus rhythm, and (3) atrial arrhythmia recurrence patterns using serial Holter electrocardiography. The latter aspect is of special importance as dronedarone may be used in paroxysmal and persistent but not permanent AF.
Methods
From January 2010 to March 2011, 120 consecutive patients with AF or non-isthmus-dependent atrial flutter (AFLA; determined on the basis of standard criteria using flutter wave morphology on 12-lead electrocardiography) were enrolled in our dronedarone registry ( Table 1 ).
| Variable | Value |
|---|---|
| Age (yrs) | 67 ± 9 |
| Women | 64 (53%) |
| Paroxysmal AF | 30 (25%) |
| Paroxysmal AFLA | 11 (9%) |
| Persistent AF | 61 (51%) |
| Persistent AFLA | 18 (15%) |
| Arrhythmia history (mos) | 73 ± 81 |
| Body mass index (kg/m 2 ) | 30 ± 5 |
| Left ventricular ejection fraction (%) | 58 ± 8 |
| Left atrial diameter (mm) | 45 ± 6 |
| New York Heart Association class II or III | 80 (67%) |
| Hypertension | 111 (93%) |
| Diabetes mellitus | 29 (24%) |
| Stroke | 7 (6%) |
| Coronary artery disease ∗ | 20 (17%) |
| Previous left atrial catheter ablation | 34 (28%) |
| Previous class I or III antiarrhythmic drug treatment | 23 (19%) |
| Medications at baseline | |
| β blockers | 114 (95%) |
| Calcium antagonists | 35 (29%) |
| Digitalis | 17 (14%) |
| Angiotensin-converting enzyme inhibitors or angiotensin receptor blockers | 98 (82%) |
| Statins | 57 (48%) |
| Vitamin K antagonists | 101 (84%) |
| Aspirin | 23 (19%) |
∗ Defined as stenosis >50% or occlusion of ≥1 coronary artery.
Dronedarone was initiated under continuous electrocardiographic monitoring in the hospital for 3 to 5 days. Each patient received dronedarone 400 mg twice daily. Persistent AF was defined as non-self-terminating AF lasting ≥7 days. If no spontaneous conversion to sinus rhythm occurred after initial dronedarone treatment, electrical cardioversion was performed. Follow-up visits were performed after 4 weeks and after 6 to 9 months. At each visit, a patient history, physical examination, laboratory tests, 12-lead electrocardiography, and 7-day Holter-electrocardiography were performed. Laboratory testing included assessments of renal and liver function.
The primary outcome was the incidence, timing, and reasons for discontinuation of dronedarone. Recurrence of AF or AFLA was defined as atrial arrhythmia lasting ≥30 seconds. Clinical inefficacy was deemed if AF-related symptoms did not improve and/or AF became permanent. Atrial arrhythmia recurrence patterns were analyzed from electrocardiographic recordings.
Results are expressed as frequencies or as means ± SD. Statistical analysis was performed on the intention-to-treat and on the on-treatment populations. Continuous data were compared using paired Student’s t tests and categorical data using chi-square tests. A p value <0.05 was considered statistically significant.
Results
Dronedarone prolonged the corrected QT interval from 409 ± 65 to 417 ± 29 ms after 3 to 5 days (p = 0.25 vs baseline) and to 423 ± 39 ms after 4 weeks (p = 0.03 vs baseline). Serum creatinine increased from 0.95 ± 0.21 to 1.07 ± 0.36 mg/dl after 3 to 5 days (p <0.001 vs baseline) and to 1.04 ± 0.32 mg/dl after 4 weeks (p <0.001 vs baseline).
After 3 to 5 days of drug treatment, 19 patients (16%) required discontinuation because of inefficacy (i.e., failed electrical cardioversion; n = 7 [6%]) or adverse events (n = 12 [10%]). After 4 weeks, 44 patients (37%) had stopped dronedarone because of inefficacy (n = 27 [23%]) or adverse events (n = 17 [14%]). After 6 to 9 months, 25 patients (21%) had discontinued dronedarone because of inefficacy (n = 16 [13%]) or adverse events (n = 9 [8%]). Overall, dronedarone was still used after 6 to 9 months in 32 patients (27%) ( Figure 1 ). In summary, discontinuation was due to inefficacy in 50 patients (42%) and to adverse events in 38 patients (32%). Adverse events requiring discontinuation are listed in Table 2 .
| Adverse Event | n (%) |
|---|---|
| Bradycardia/atrioventricular block | 10 (8) |
| QT-interval prolongation | 5 (4) |
| Gastrointestinal side effects | 6 (5) |
| Exanthema/erythema | 5 (4) |
| Increases in hepatic enzymes | 3 (3) |
| Increases in renal laboratory values/acute renal failure | 4 (3) |
| Muscle spasm | 2 (2) |
| Sleep disturbance | 1 (1) |
| Edema of the extremities | 1 (1) |
| Hyperthyroidism | 1 (1) |
After 4 weeks and 6 to 9 months, maintenance of sinus rhythm was achieved in 40 (33%) and 24 (20%) patients, respectively. Among 34 patients who had previously undergone left atrial catheter ablation, sinus rhythm was maintained in 13 (38%) and 8 (24%) after 4 weeks and 6 to 9 months, respectively. Among the 23 patients with previous class I or III antiarrhythmic drug treatment, sinus rhythm was maintained in 5 (22%) and 4 (17%) after 4 weeks and 6 to 9 months, respectively ( Table 3 ).
