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Ibutilide is the first pure class III drug that has become clinically
available. Its effects on repolarization are due both to activation of slow Na+ inward current and blockade
of the rapid component of inward rectifier potassium current (IKr)10. The results of 5 clinical trials have been
published11-15 (Tab. I). The mean times to conversion were between 13 and 31 minutes. No significant side
effects were observed except for ventricular tachycardias, mainly torsades de pointes, that were mostly non
sustained – responding to drug withdrawal and/or magnesium sulfate infusion – but required electrical
cardioversion in about 2% of the cases.
In summary: a) the success of ibutilide was clearly superior to any previous antiarrhythmic agent in atrial
flutter (around 60%); b) in acute atrial fibrillation ibutilide converted no more than 30-40% of the patients
(less than IC drugs); however c) it converted a lower but significant percentage of patients with a chronic
arrhythmia, where the classical antiarrhythmic drugs are virtually useless. This was particularly evident for
atrial flutter but still detectable for atrial fibrillation, particularly with high dosages (2 mg in 10 min)15.
Table II – Summary of the results of the published trials of intravenous dofetilide in atrial fibrillation
Author, year published
|
Dofetilide dosage
|
Converted patients/
total patients (%)
|
NSVT/total (%)
|
TdP/total (%)
|
DC shock (%)
|
|
|
Atrial fibrillation
|
Atrial flutter
|
Suttorp 1992 17
|
2.5-8 mg/kg
|
10/19 (53)
|
4/5 (80)
|
0/24 (0)
|
0/24 (0)
|
0/24 (0)
|
Crjins 1994 18
|
4-8 mg/kg
|
|
7/10 (70)
|
0/10 (0)
|
0/10 (0)
|
0/10 (0)
|
Sedgwick 1995 19
|
8-12 mg/kg
|
4/15 (27)
|
|
0/15 (0)
|
2/15 (13.3)
|
Not reported
|
Frost 1997 20
|
4-8 mg/kg
|
26/65 (40)
|
|
3/65 (4.5)*
|
0/65 (0)
|
0/65 (0)
|
Falk 1997 21
|
4-8 mg/kg
|
7/50 (14)
|
6/11 (54)
|
2/61 (3.2)
|
2/61 (3.2)
|
0/61 (0)
|
Bianconi 1999 22
|
8 mg/kg
|
8/36 (22)
|
9/12 (75)
|
2/48 ( 4.2)
|
4/48 (8.3)
|
1/48 (2.1)
|
Total trials
|
|
55/185 (30)
|
27/38 (71)
|
7/223 (3.1)
|
8/223 (3.6)
|
1/208 (0.5)
|
* 3 patients had atrial flutter; NSVT = non sustained ventricular tachycardia; TdP = torsades de
pointes; DC shock = torsade de pointes requiring DC shock.
Ibutilide, despite not proven to be a wonder drug, may have a place in the antiarrhythmic armamentarium.
It can be used to stop acute atrial fibrillation where other drugs are contraindicated (e.g. in patients with
heart failure or with excitability or conduction disorders) and it can also be considered first-choice drug for
the cardioversion of atrial flutter. Given the risk of torsades des pointes, the use of ibutilide is restricted to
a hospital environment with a defibrillator at hand.
Dofetilide is a highly specific blocker of IKr16. Six clinical trials
on its intravenous use are available (Table II)18-23.
As for ibutilide, the arrhythmia duration does not significantly affect the outcome of therapy. In the only study
on recent onset atrial fibrillation20, carried out immediately after coronary surgery, dofetilide was not
significantly better than placebo in conversion to sinus rhythm (40 versus 24%).
Overall, the efficacy and safety profile of intravenous dofetilide is similar to that of ibutilide.
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