Division of Cardiology, University of Maryland School of Medicine, Baltimore, MD, USA
* Correspondence to: Ijaz A. Khan, Division of Cardiology, University of Maryland School of Medicine, 22 South Greene Street, S3B06, Baltimore, MD 21201, USA. Tel.: +1-410-328-2251; fax: +1-410-328-2255
E-mail address: ikhan{at}medicine.umaryland.edu
This editorial refers to "Flecainide versus ibutilide for immediate cardioversion of atrial fibrillation of recent onset"1 by J. Reisinger et al. on page 1318
Atrial fibrillation is the most common, clinically relevant arrhythmia with a prevalence of about 2% in the general population. The symptoms in atrial fibrillation are primarily caused by fast ventricular rates, which can be controlled by using the atrio-ventricular node blocking drugs or, even more effectively, by converting atrial fibrillation to sinus rhythm. Although the traditional treatment options available to treat atrial fibrillation are rhythm control versus ventricular rate control, the best method to control ventricular rate, however, is by conversion to sinus rhythm. Even though the reported rate of spontaneous conversion is up to 50%, in the first 24 h after the onset of atrial fibrillation, the earlier restoration of sinus rhythm by cardioversion will result in an early alleviation of the patient's symptoms, will eliminate the need for the use of atrio-ventricular node blocking drugs for rate control, will decrease the chances of thromboembolism, will prevent tachycardia-related cardiomyopathy, and will lessen atrial mechanical dysfunction and electrophysiological remodelling. Atrial electrophysiological remodelling, which begins to take place within a few hours of the initiation of atrial fibrillation, results in a decreased atrial refractoriness that may facilitate atrial fibrillation and decrease the chances of successful cardioversion. Moreover, the post-conversion atrial stunning, a phenomenon clearly responsible for post-conversion thromboembolism, is also related to the duration of atrial fibrillation, which makes the case even stronger for an early conversion to sinus rhythm.1 Therefore, if it is decided to restore sinus rhythm, why not attempt it as soon as possible?
The most efficient and immediate method of atrial fibrillation cardioversion is by direct electric current, which is successful in 8090% of cases. The potential drawbacks of direct current cardioversion include the need for anaesthesia, aspiration risk, pain, skin burning, pulmonary oedema, pacemaker malfunction, the patient's anxiety of receiving electric current, and adverse cardiac effects such as sinus arrest and ventricular fibrillation.2,3 Pharmacological cardioversion, on the other hand, is less effective than the electrical cardioversion with a success rate of 6080% but has advantages of being simple and convenient, free of the need for anaesthesia and being feasible in recent post-prandial state. The potential disadvantages include drug-related side effects and lack of effect in chronic atrial fibrillation. The drugs that have been tested for cardioversion of recent onset atrial fibrillation include Singh and Vaughan Williams class IA (quinidine, procainamide, disopyramide), class IC (flecainide, propafenone), and class III (ibutilide, dofetilide, sotalol, amiodarone) anti-arrhythmic agents, both by oral and intravenous routes.3,4 In general, all of these drugs work by prolonging atrial refractoriness.
Historically, quinidine was the first oral anti-arrhythmic drug and procainamide was the first intravenous anti-arrhythmic drug used for conversion of atrial fibrillation to sinus rhythm. Quinidine use for this purpose was started in the first quarter of the 20th century.5 Since then it has been used in single loading doses or graduated loading doses. The conversion rates of 2488% have been reported with rates in higher ranges by graduated loading dose regimens. The major limitations of the use of quinidine are its intolerable gastrointestinal side effects, precipitation of heart failure in patients with systolic dysfunction, and a potential to prolong the QT interval and precipitate torsade de pointes type polymorphic ventricular tachycardia. In the 1980s, intravenous procainamide was used for cardioversion of atrial fibrillation. The conversion rates with procainamide have ranged from 43% to 75%. Profound hypotension, precipitation of heart failure, and a high potential of developing long QT interval and torsade de pointes has made procainamide a less favorable drug. Use of both quinidine and procainamide requires concomitant use of atrioventricular node blocking drugs to prevent a possible increase in ventricular rates caused by an acceleration of atrioventricular node conduction. Disopyramide has been tested for cardioversion of atrial fibrillation in only one study; therefore, a case cannot be made for the use of disopyramide in clinical practice for this purpose.4
Class IC anti-arrhythmic drugs, flecainide and propafenone, are generally considered to be better than class IA anti-arrhythmics for the cardioversion of atrial fibrillation because of their higher success rates and favourable adverse effect profile.6,7 Both flecainide and propafenone can be used orally as well as intravenously. The efficacy is comparable between both drugs as well as between both routes of drug administration but intravenous administration takes less time to conversion. Success rates of up to 91% have been reported with flecainide and of up to 83% with propafenone depending on the duration of follow-up after drug administration. The conversion time by oral routes ranges from 2 to 4 h and intravenously it is about the half. The side-effect profile of class IC drugs is more favourable as these drugs do not prolong the repolarisation phase of the cardiac action potential and thus, do not precipitate torsade de pointes. Nonetheless, class IC drugs prolong the depolarisation, which may result in transient widening of the QRS complex and conduction disturbances. Also, there is a possibility that one to one atrio-ventricular conduction may occur in case atrial flutter develops but it is rare. Although the need of a concomitant use of atrioventricular node blocking drugs has not been thoroughly evaluated, it might be practical to use such drugs, especially when using flecainide because flecainide lacks the beta-adrenergic blocking and calcium channel blocking effects inherent in propafenone.
Among class III drugs, ibutilide is used by the intravenous route and dofetilide by the oral route. The reported efficacy of these agents ranges from 20% to 75% depending on the duration of atrial fibrillation and the duration of follow up after drug administration.4 The potential concern with the use of these medications is prolongation of the QT interval and a high prevalence of torsade de pointes, which should preclude the use of these agents in a non-monitored environment. Efficacy of sotalol for conversion of atrial fibrillation is modest. Amiodarone has been used both intravenously and orally for cardioversion of the recent-onset atrial fibrillation.8 Intravenous amiodarone has been used as a bolus only or as a bolus followed by a continuous intravenous infusion until conversion or up to 24 h. The reported efficacy is 3469% with the bolus-only regimens, and 5595% with the bolus followed by infusion regimens. In trials, only the higher doses of more than 1500 mg/day of amiodarone have been shown to be superior to the placebo in converting recent onset atrial fibrillation to sinus rhythm, but no clear dose regimen has been established for routine clinical use.
A major limitation of the studies on the pharmacological cardioversion is an extensive list of exclusion criteria used in most of these studies, which preclude the implementation of their results in the general patient population. Patients with unstable or advanced structural heart disease have been excluded from most of these studies. Furthermore, most of the studies on pharmacological cardioversion of atrial fibrillation are either observational or lack a placebo arm, which makes the evaluation of the drug efficacy difficult because, as time elapses, more and more patients convert spontaneously to sinus rhythm. Consequently, it might not be possible to separate the drug effect from spontaneous conversions, especially at the later parts of the follow-up, and probably that is how the length of the follow-up period after drug administration becomes an important determinant of the efficacy of the drug. Therefore, to minimise the superfluous effect of spontaneous conversion on drug efficacy, it would be practical to limit the follow-up time to 23 half lives of the drug after the last administered dose in trials evaluating drug efficacy, even in those placebo-controlled.
In this issue of the European Heart Journal, Reisinger et al.9 report the efficacy and safety of intravenous flecainide and intravenous ibutilide for cardioversion of recent onset atrial fibrillation in a well conducted, multi-centre, randomised, comparative but non-placebo-controlled trial including 207 patients with atrial fibrillation of 48 h or less. Flecainide was given over 20 min at a dose of 2 mg/kg body weight (maximum 200 mg) and ibutilide was infused at a dose of 1 mg (or 0.01 mg/kg if less than 60 kg) over 10 min, followed by a 10 min observation period and an identical second dose if atrial fibrillation did not convert to sinus rhythm. The follow-up period for the evaluation of drug efficacy was 90 min. Generally, the rate of spontaneous conversion of the recent onset atrial fibrillation is around 20% within the first 90 min. According to this trial, there was no difference in the efficacy of both drugs with conversion rates of 56% in patients given flecainide and 50% in patients given ibutilide. The adverse events were mild and reversible, with equal frequency in both treatment groups. As indicated by a post hoc analysis, the flecainide administration was more than 30 times cost-effective when compared to ibutilide. Similar to most of the other trials on the subject of pharmacological cardioversion, the exclusion criteria in this trial were also extensive. Surprisingly, many of the previously known predictors of conversion of atrial fibrillation, including left atrial size and left ventricular systolic function, were not of significance in this trial population. Two mechanisms could be speculated for this contrary finding: first, it could be the powerful effect of the intravenous administration of drugs that dominated the positive outcome, irrespective of the co-variables present in the patients, and second, extensive exclusions might have diluted the predictive effect of even the well-known predictors. Another perplexing point in this trial is that the efficacy of intravenous flecainide is lower than that shown in the previous trials; a speculative reason for which could be the longer infusion time of 20 min selected in this trial, whereas, the infusion time of flecainide has been 10 min in other trials.1012
While using the results of this trial in clinical practice, provided it is decided to attempt an intravenous pharmacological cardioversion after fulfilling the long list of exclusions set forth in the trial and the choice is between using either flecainide or ibutilide, it would be more practical to use intravenous flecainide because it is at least as effective as ibutilide but without the risk of torsade de pointes and is much more cost-effective. A 10 min infusion time should be preferred since it has been shown to be of higher efficacy: after all, the aim of any drug use is to assert its optimal benefits.
Footnotes
References
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