Ibutilide is a class III antiarrhythmic agent indicated for cardioversion of atrial fibrillation and atrial flutter to sinus rhythm (SR). The most serious complication of ibutilide is torsades de pointes (TdP). Magnesium has been successfully used for the treatment of TdP, but its use as a prophylactic agent for this arrhythmia has not yet been established. The present study investigated whether high dose of magnesium would increase the safety and efficacy of ibutilide administration. A total of 476 patients with atrial fibrillation or atrial flutter who were candidates for conversion to SR were divided into 2 groups. Group A consisted of 229 patients who received ibutilide to convert atrial fibrillation or atrial flutter to SR. Group B consisted of 247 patients who received an intravenous infusion of 5 g of magnesium sulfate for 1 hour followed by the administration of ibutilide. Then, another 5 g of magnesium were infused for 2 additional hours. Of the patients in groups A and B, 154 (67.3%) and 189 (76.5%), respectively, were converted to SR (p = 0.033). Ventricular arrhythmias (sustained, nonsustained ventricular tachycardia, and TdP) occurred significantly more often in group A than in group B (7.4% vs 1.2%, respectively, p = 0.002). TdP developed in 8 patients (3.5%) in group A and in none (0%) in group B (p = 0.009). The administration of magnesium (despite the high doses used) was well tolerated. In conclusion, the administration of high doses of magnesium probably makes ibutilide a much safer agent, and magnesium increased the conversion efficacy of ibutilide.
The most serious complication of ibutilide administration is torsades de pointes (TdP), due to QT prolongation, which should preclude its use a nonmonitored environment. TdP occurs in approximately 4% of patients receiving ibutilide. Magnesium supplementation has been successfully used for the treatment of TdP and might also control other cardiac (ventricular and supraventricular) arrhythmias, particularly in hypomagnesemic patients. Prophylactic administration of intravenous magnesium sulfate seems to prevent the increases in the QT and QTc interval after the last infusion of ibutilide and to protect against the development of TdP. Prevention of QTc prolongation with low doses of magnesium in patients receiving another class III antiarrhythmic agent, such as sotalol or dofetilide, was also reported, and the use of intravenous magnesium enhanced the ability of dofetilide to successfully convert atrial fibrillation or atrial flutter. Although magnesium has been also tested in patients with atrial fibrillation or atrial flutter, improving the efficacy of ibutilide to successfully cardiovert, its routine administration has not yet been established. Additionally, no clear dose regimen has been established for clinical use. Thus, we conducted the present study to investigate whether high doses of magnesium would increase the safety and efficacy of ibutilide administration in this population.
Methods
The study included 476 consecutive patients, who had been admitted to either general hospital (Konstantopoulio General Hospital and KAT General Hospital of Attica) during the past 4 years, and had had a recent onset (previous 48 hours) of atrial fibrillation or atrial flutter. The patients were divided into 2 groups. Group A served as the control group and consisted of 229 patients who received ibutilide (intravenous infusion of 1 mg for 10 minutes and a second intravenous infusion of 1 mg for another 10 minutes, with a 10-minute interval between the 2 infusions) to convert atrial fibrillation or atrial flutter to SR. The second infusion was omitted if SR had already been achieved. Group B, the study group, consisted of 247 patients who received an intravenous infusion of 5 g of magnesium sulfate for 1 hour followed by the administration of ibutilide using the same protocol as in group A. After completion of the 5-g intravenous infusion of magnesium sulfate, another 5 g of the same agent was infused for 2 additional hours, using another vein, without interrupting the ibutilide infusion protocol. Patients with QTc (corrected QT interval) >500 ms after the first infusion of ibutilide were not given the second dose. If within 4 hours, SR was not achieved, the case was recorded as a failure of ibutilide.
A complete medical history, physical examination, routine laboratory results (including thyroid function tests), 12-lead electrocardiogram, and an echocardiogram were obtained at the baseline evaluation. The cardiac rhythm was monitored continuously for 8 hours after starting the medication. A 12-lead electrocardiogram was recorded after the first and second infusion of ibutilide, at the conversion to SR, or at the appearance of a significant rhythm change.
The exclusion criteria were clinical signs of congestive heart failure (New York Heart Association functional class greater than II), severely reduced left ventricular systolic function (left ventricular ejection fraction <35%), evidence of an acute ischemic insult, myocardial infarction within the preceding 6 weeks, hypotension (systolic blood pressure <90 mm Hg), sick sinus syndrome (unless protected by a permanent pacemaker), prolongation of the QTc to >450 ms, renal dysfunction (i.e., serum creatinine >2.5 mg/dl), hepatic insufficiency, uncorrected hypokalemia or hypomagnesemia, and known ibutilide hypersensitivity.
All patients gave written informed consent for the procedure, and the local scientific committee for human research approved the study protocol.
Continuous variables are presented as proportions and as the mean ± SD and were compared between the 2 groups using the Student t test. A p value <0.05 was considered statistically significant.
Results
No differences were seen in age, gender, or the other characteristics between the patients who received only ibutilide and those who also received magnesium. The end-diastolic diameter, global left ventricular function, and left atrial diameter were also similar ( Table 1 ).
| Variable | Ibutilide Alone (n = 229) | Magnesium Plus Ibutilide (n = 247) | p Value |
|---|---|---|---|
| Age (years) | 58.3 ± 19.2 | 62.4 ± 26.8 | 0.057 |
| Men | 155 (67.8%) | 160 (64.8%) | 0.552 |
| Left atrium (cm) | 4.31 ± 0.91 | 4.19 ± 0.78 | 0.122 |
| Left ventricle ejection fraction (%) | 50.4 ± 13.2 | 52.4 ± 14.8 | 0.121 |
| Left ventricle end-diastolic diameter (cm) | 5.20 ± 1.24 | 4.98 ± 1.31 | 0.061 |
| Hypertension | 120 (52.4%) | 136 (55%) | 0.634 |
| Previous atrial fibrillation | 159 (69.4%) | 185 (74.8%) | 0.226 |
| Diuretic use | 87 (38%) | 84 (34%) | 0.416 |
| β-Blocker use | 123 (53.7%) | 118 (47.7%) | 0.224 |
| Amiodarone use | 30 (13.1%) | 27 (10.9%) | 0.550 |
| Digoxin use | 67 (29.2%) | 84 (34%) | 0.350 |
| Calcium channel blocker use | 64 (27.9%) | 83 (33.6%) | 0.213 |
| Angiotensin-converting enzyme inhibitor or angiotensin receptor blocker use | 107 (46.7%) | 104 (42.1%) | 0.359 |
Of the 229 patients in group A and the 247 patients in group B, 154 (67.3%) and 189 (76.5%) were converted to SR (p = 0.033). Therefore, with the addition of magnesium, a 13.7% improvement in the success rate of ibutilide was realized.
The maximum QTc did not differ between the 2 groups (443.2 ± 47.8 ms for group A vs 436.7 ± 36.4 ms for group B, p = 0.094); however, the increase in the QTc was lower in the magnesium group (51.2 ± 26.5 ms vs 45.8 ± 20.4 ms, p = 0.013).
Ventricular arrhythmias (sustained, nonsustained ventricular tachycardia, and TdP) occurred significantly more frequently in group A. TdP developed in 8 patients (3.5%) in group A and in no patient (0%) in group B (p = 0.009; Table 2 ).
| Variable | Ibutilide Alone (n = 229) | Magnesium Plus Ibutilide (n = 247) | p Value |
|---|---|---|---|
| Nonsustained ventricular tachycardia | 13 (1.3%) | 2 (0.8%) | 0.93 |
| Sustained ventricular tachycardia | 6 (2.2%) | 1 (0.4%) | 0.11 |
| Torsades de pointes | 8 (3.9%) | 0 (0%) | 0.009 |
| Total ventricular arrhythmias | 17 (7.4%) | 3 (1.2%) | 0.002 |
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