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The currently available drugs for restoring and maintaining sinus
rhythm in patients with atrial fibrillation are far from ideal.
Class IC antiarrhythmic agents have a good success rate in terminating acute atrial fibrillation, while they are
virtually ineffective in the chronic form of the arrhythmia1-3. Moreover – due to their depressant effects on
myocardial contractility and conduction – their use is precluded in patients with cardiac insufficiency or
excitation-conduction disturbances. Intravenous amiodarone has not these drawbacks, but its onset of
action is very slow, rendering the drug useless for a rapid conversion of the arrhythmia4.
Class IA antiarrhythmic agents (quinidine, procainamide and disopyramide) have an efficacy in maintaining
sinus rhythm after cardioversion not exceeding 50% at one-year and their use is limited by the frequent
occurrence of systemic side effects. Moreover, their safety has been questioned since the long-term
treatment with quinidine was found to be associated with increased mortality respect to placebo5.
Other drugs, pertaining to class IC and III are better tolerated (propafenone, flecainide and sotalol), more
effective (amiodarone) and probably safer (all of them) than class IA agents6. However, class IC agents
and sotalol are not more effective than quinidine and have depressant effect on myocardial contractility,
while amiodarone is burdened by a high incidence of systemic side effects7.
Table I – Summary of the results of the published trials of intravenous ibutilide in atrial fibrillation
Author, year published
|
Ibutilide dosage
|
Number of converted
patients/total (%)
|
NSVT/total (%)
|
TdP/total (%)
|
DC shock (%)
|
Atrial fibrillation
|
Atrial flutter
|
Stambler 1996 11
|
1 mg/10 min + 0.5-1mg/10 min
|
25/81 (31)
|
50/80 (63)
|
7/180 (3.9)
|
15/180 (8.3)
|
3 (1.7)
|
Ellenbogen 1996 12
|
0.015-0.025 mg/kg/10 min
|
23/78 (29)
|
30/79 (38)
|
Not reported
|
6/157 (3.8)
|
4 (2.5)
|
Abi-Mansour 1998 13
|
1 mg/10min + 1mg/10 min
|
46/164 (28)
|
27/45 (61)
|
8/219 (3.6)
|
14/219 (6.4)
|
4 (1.9)
|
Volgman 1998 14
|
1 mg/10min + 1mg/10 min
|
22/43 (51)
|
13/17 (76)
|
1/60 (1.7)
|
1/60 (1.7)
|
1 (1.7)
|
Vos 1999 15
|
1-2 mg/10 min
|
55/169 (33)
|
23/36 (64)
|
13/211 (6.2)
|
2/211 (0.9)
|
1 (0.5)
|
|
Total trials
|
|
171/535 (32)
|
143/257 (56)
|
29/670 (4.3)
|
38/827 (4.6)
|
13/827 (1.6)
|
NSVT = non sustained ventricular tachycardia; TdP = torsades de pointes; DC shock = torsade de pointes
requiring DC shock.
It is clear that new drugs more effective and, most important, devoid of systemic and cardiac untoward
effects are strongly desirable.
The recent advances in understanding of the electrophysiological basis of atrial fibrillation have identified
the short atrial refractory period associated with atrial fibrillation as the “vulnerable parameter” of the
arrhythmia8. On this basis, in the last decade, the research has focused on the development of drugs
specifically prolonging the refractory period by acting on repolarization. There has been a great deal of
expectation on these new compounds, also because they emerged as virtually devoid of undesirable
effects on cardiac contractility, excitability and conduction and this would allow their use even in patients
in whom other antiarrhythmic drugs are precluded9.
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