G. CHIARANDÀ1, M.L. CAVARRA1, C.L. ROMEO1, M. CHIARANDÀ1, T. REGOLO2
Atrial fibrillation (AF) is the most common cardiac arrhythmia in the gener- al population, with a prevalence ranging from 0.5% to 9% between the ages of 50 and 80 years. Literature data [1] suggest that the incidence of this arrhythmia increases dramatically in patients with heart failure. AF can cause a rise in morbidity and mortality due to the loss of atrial function and the consequent decrease in heart performance and increase in embolic risk Moreover, a persistently elevated ventricular rate during AF can produce dilated ventricular cardiomyopathy. For these reasons, recovery and mainte- nance of sinus rhythm is one of main objectives of treatment.
A series of anti-arrhythmic agents have been demonstrated to be highly effective in terminating recent-onset AF; however, the results obtained in preventing recurrences are scanty [2, 3]. The anti-arrhythmic agents most used in Europe are class IA disopyramide and quinidine, class IC flecainide and propafenone, and class III amiodarone and sotalol. Table 1 summarises reported data from the literature.
The percentage of patients who maintain sinus rhythm without arrhyth- mia recurrence under placebo treatment is around 30% after 6 months and 25% after 12 months. Anti-arrhythmic agents can may increase the percent- age of patients in sinus rhythm, but the overall efficacy is limited. No more than 50% of treated patients are free from arrhythmia recurrences after 12 months; only for amiodarone do the efficacy rates range from 50% to 73% at 12 months. Of course, the final result may be influenced by the selection of the patient population, the types of AF, and the way in which anti-arrhyth- mic agents are begun.
1Coronary Care Unit, Muscatello Hospital, Augusta (Syracuse);2Coronary Care Unit, Ferrarotto University Hospital, Catania, Italy
We should consider an increase in time to first recurrence or time in sinus rhythm as a good primary result in order to ameliorate the possible haemodynamic complications of AF. Many variables affect the maintenance of sinus rhythm and the efficacy or not of the anti-arrhythmia therapy:
- Duration of the arrhythmia (from the literature there appears a cut-off at between 6 months and 2 years)
- Left atrial size (from >45 mm to > 60 mm) (this variable is not yet accepted by everybody because the atrial enlargement could be a conse- quence rather than the cause of the arrhythmia)
- Early recurrence of the arrhythmia
- The presence of a severe valvular rheumatic disease - Advanced NYHA functional class
- The presence of a cardiopathy (for example, a hypertensive cardiopathy) - Advanced age
- Doppler echo cardiog raphic index [A wave peak and integ ral velocity/time soon after electrical cardioversion (ECV), fibrillation wave peak during auricular filling and emptying before ECV; early left auricu- lar end-diastolic or diastolic length] [4, 5].
Class I Anti-arrhythmic Agents
Class I anti-arrhythmic drugs have been shown to be superior to placebo, but there are contrasting data because they were often tested in small studies involving patients with different clinical features. On the whole, they are effec- tive in preventing AF recurrences in about 40–50% of patients after 12 months.
Table 1.Drugs for prevention of atrial fibrillation recurrence: success in sinus rhythm maintenance following cardioversion of atrial fibrillation
Drugs Sinus rhythm
At 1 month At 3 months At 6 months At 12 months
(%) (%) (%) (%)
Placebo 58 15–56 19–35 0–43
Quinidine 65 44–75 27–58 23–51
Disopyramide – 72 45–50 55
Propafenone 54 44 40 –
Flecainide – 44 – 34–42
Dofetilide – 58–44 51–71 40–66
Sotalol – 49–50 46–50 37–46
Amiodarone – – 75–78.5 50–73
Quinidine is effective in maintaining sinus rhythm (Table 1). However, its use is limited by the demonstrated high risk for torsades de pointes and the mortality rate (total mortality at 1 year with quinidine 2.9% vs. control group 0.8%) [6].
Two placebo-controlled studies supported the efficacy of flecainide in increasing time to first AF recurrence and reducing AF burden [7, 8]. Other randomised studies evidenced comparable efficacy to that of quinidine, cou- pled with fewer side effects [9, 10]. Flecainide (200 mg daily) was shown to be effective in postponing the first recurrence of AF, and superior to long- acting quinidine (1100 mg daily) without the occurrence of severe side effects or pro-arrhythmia [11].
Compared with placebo, propafenone also increased the overall time free from AF and the interval to first recurrence [6, 12]. In an open-label ran- domised study involving 100 patients with AF, propafenone and sotalol were similar in preventing AF episodes (30% vs 37%, respectively) [13].
Class IC drugs may be initiated out of hospital: in a selected risk-strati- fied population with recurrent AF, ‘pill in the pocket’ treatment is feasible and safe, with a high rate of patient compliance and low adverse event rate, and markedly reduces hospital admissions [14].
Class III Anti-arrhythmic Agents
Amiodarone and sotalol are the most frequently used class III drugs for maintaining sinus rhythm in patients with AF [15].
The efficacy of sotalol seems to be similar to that of class I drugs. The ventricular rate during AF recurrences is attenuated and the haemodynamic pattern of AF recurrences is better after sotalol treatment than without. The likelihood of remaining in sinus rhythm is higher in younger patients, with a smaller left atrial size and without concomitant heart disease. Patients treat- ed with sotalol must initially be monitored with ECG (for 3 days) in hospital because of the potential pro-arrhythmic effect.
Amiodarone is the most effective anti-arrhythmic agent. A large ran- domised trial (CTAF) compared the effects of low-dose of amiodarone (200 mg daily) with conventional therapy (propafenone and sotalol) in mainte- nance of sinus rhythm during a follow-up of 1 year: 70% of patients assigned to amiodarone had no recurrence of AF and the amiodarone was superior to class I drugs [16].
In the randomised CHF-STAT trial amiodarone was used in order to eval- uate its effects on mortality in patients with heart failure. The drug showed a significant potential to convert AF to sinus rhythm, and prevented the devel- opment of new-onset AF [6].
In a cohort of post-cardioversion patients the group treated with amio- darone showed a significantly lower incidence of AF relapses in comparison with quinidine and was coupled with fewer side effects [17].
The efficacy of amiodarone for maintenance of sinus rhythm has been supported by many studies, but the relatively high incidence of side effects [18] justifies its common use as a second-line or last-resort option, with the important exception of heart failure.
Other Drugs
Dofetilide, a new anti-arrhythmic agent approved for use in the USA but not in Europe, is effective in preventing AF and atrial flutter. Two large-scale and double-blind randomised studies have supported its efficacy: the SAFIRE-D and EMERALD studies [19, 20]. Sixty-six of patients in the SAFIRE and 71%
of patients in the EMERALD study were free from AF relapses, compared with 21–25% in the placebo group and 60% in the sotalol group.
Beta-blockers are generally not included among the anti-arrhythmic agents; however, metoprolol has demonstrated a good rate of maintaining persistent sinus rhythm as compared with placebo (51% vs 40%; P < 0.05) and can be considered in some clinical situations, especially in the postoper- ative protocols of myocardial revascularisation for patients with no con- traindications for its use [21, 22].
Dronedarone shares the electrophysiological properties of amiodarone:
at 800 mg daily dose, it appears to be effective and safe for the prevention of AF relapses after cardioversion [23]. The absence of thyroid side effects and of pro-arrhythmia are important feature of the drug, but further studies are needed.
Role of Pharmacological Pre-treatment in Reducing AF Recurrences
The most relevant clinical problem after successful cardioversion is the risk of recurrences resulting from fibrillation-induced electrical remodelling of the atrium. The recurrences may occur acutely in the very early phase (min- utes), or in the subacute phase, or they may be early recurrences (from 24–48 h to 7–14 days), or, in the weeks to months range, they may be late. The effi- cacy of pre-treatment with class I and III anti-arrhythmic drugs in prevent- ing acute and subacute AF recurrences has been reported [24, 25].
Recently the role of the verapamil alone or combined with another anti- arrhythmic drugs has been investigated. The VERAF study clearly demon- strated that verapamil alone, in patients who were not taking anti-arrhyth-
mic agents at the time of cardioversion, is highly effective in reducing very early and early recurrences of AF after successful cardioversion, but is inef- fective in the long run [26]. The VEPARAF study suggested that oral vera- pamil administration, combined with a class IC or III anti-arrhythmic drug, is effective in reducing both primary and secondary recurrences after car- dioversion [27].
Angiotensin Antagonist Receptors
A recent study has shown that irbesartan combined with amiodarone was more effective than amiodarone alone in the prevention of AF recurrences after ECV [28]. In our experience, candesartan combined with class IC drugs has reduced the numbers of relapses and the time to first relapse of AF after effective ECV [29].
Pro-arrhythmic Effects
Today there is major concern over the risk of potentially fatal ventricular pro-arrhythmic effects caused by drugs employed for a relatively benign arrhythmia such as AF.
Sotalol may cause torsades de pointes, but the risk is dose-dependent (1%
for dosage between 160 and 240 mg daily and 4–5% for a dosage higher than 480 mg daily), and torsades de pointes may b e precipitated by hypokalaemia, bradycardia, reduced creatinine clearance, and other drugs inducing CT prolongation.
The prevalence of torsades de pointes is lower with amiodarone (less than 1% despite frequently marked QT prolongations). However, the use of amiodarone is limited by other side effects (skin discoloration 4.5%, pul- monary fibrosis 3.6%, thyroid abnormalities 2.7%). The mortality rate asso- ciated with amiodarone treatment is around 0.6%, comparable to that of control patients.
Class IC drugs have a marked effect on conduction velocity and may organise and slow the rate of AF, converting it into atrial flutter. The pro- arrhythmic effect is favoured by adrenergic stimulation and has been report- ed in 3–5% of patients treated with flecainide or propafenone; patients with significant left ventricular dysfunction are potentially at higher risk.
Some categories of patients are at higher risk of pro-arrhythmia: those with previous myocardial infarction, overt or previous congestive heart fail- ure, significant left ventricular dysfunction, previous conduction disease, or electrolyte impairment, or those of advanced age.
Choice of Anti-arrhythmic Drugs
The choice of one anti-arrhythmic drug rather than another one depends on the risk/benefit ratio relating to specific aspects: (a) underlying cardiopathy and degree of left ventricular systolic dysfunction; (b) pharmacokinetics, phar- macodynamics, electrophysiological characteristics, and mode of action; (c) possible haemodynamic effects; (d) pro-arrhythmic risks and side effects.
In general, in patients with no or minimal structural heart disease, class IC drugs or sotalol appear to be the first-line choice.
In patients with hypertension with no or minimal left ventricular hyper- trophy, or in patients with a high resting sinus rate, or with adrenergically mediated AF, sotalol or other beta-blockers could represent the first-line choice. In patients with severe left ventricular hypertrophy or valvular heart disease the first-line choice is amiodarone.
In the presence of ischaemic heart disease, or left ventricular dysfunc- tion, in patients with very frequent AF recurrences or large right or left atria, or with a long history of AF, amiodarone is the anti-arrhythmic drug of choice. In patients with vagally mediated AF, the use of drugs with vagolytic action such flecainide or disopyramide is suggested.
Finally, in some clinical situations there is no indication for any anti- arrhythmic drug: (a) after the first episode, unless there is significant haemodynamic impairment; (b) when AF is well-tolerated, short-lasting, and self-limited; (c) when AF occurs during acute myocardial infarction or other acute conditions; (d) when AF occurs just after cardiac surgery, unless there is a history of previous AF attacks.
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