Pharmacological Treatment For Atrial Fibrillation
Pharmacological cardioversion of AF can be achieved using a number of drugs with different pharmacological properties, including disopyramide, procainamide, quinidine (all class IA), ﬂecainide, propafenone (both class IC), dofetilide, ibutilide, sotalol, and amiodarone (all class III). Currently, the most commonly used drugs for chemical cardioversion are ﬂecainide, sotalol, and amiodarone. Little difference is observed between the routes of administration for cardioversion rates, although intravenous administration results in faster conversion. Indeed, in patients with recent onset AF, successful cardioversion is reported in up to 80% of cases with oral therapy, rising only to 90% with intravenous administration.1
Unfortunately, recurrence of AF is common, often requiring long-term drug therapy to improve maintenance of sinus rhythm. For most current antiarrhythmic agents, the relapse rate is at least 50% during the ﬁrst year,2–5 although slightly better ﬁgures are seen with dofetilide6 and amiodarone.7,8 A number of studies have also demonstrated that ﬂecainide and propafenone are effective drugs for preventing AF recurrence.9–11 The effectiveness of ﬂecainide is comparable to quinidine, but with fewer side effects.12 In contrast, propafenone is more effective for maintenance of sinus rhythm than quinidine. It is as effective as sotalol.13,14 Generally, however, class IC drugs are preferred to class IA drugs in view of their better safety proﬁle.12,13 The success of electrical cardioversion for AF has been quoted as between 75 and 93%, although this depends on left atrial size and co-existing structural heart disease, and ultimately on the duration of AF.15–17 Where there is some concern about a successful restoration of sinus rhythm (for example, previous cardioversion failure or early recurrence of AF), concomitant amiodarone or sotalol can be used pre-cardioversion to improve the success of electrical cardioversion.18 Such an approach is advocated by the ACCF/AHA practice guidelines 2013 on AF management.2 The frequency of recurrence of AF after electrical cardioversion is high, and maintenance therapy with antiarrhythmic drugs such as amiodarone or sometimes b-blockers is somewhat useful to prevent AF relapses.1 Beta-blockers are very effective at controlling ventricular rate and also may reduce the risk of AF recurrence following successful cardioversion (whether spontaneous, pharmacological, or electrical) and are currently used as ﬁrst-line prophylactic agents in paroxysmal AF. Rate-limiting, non-dihydropyridine calcium channel blockers (diltiazem, verapamil) are frequently used to optimize rate control where B-blockers are contraindicated or ineffective. A rate-limiting calcium antagonists (diltiazem, verapamil) are indicated where urgent pharmacological rate control is required. Intravenous amiodarone is a useful alternative in situations where the administration of b-blockers or calcium antagonists is not feasible, such as in the presence of heart failure. All current class IA, IC, and III antiarrhythmic drugs have signiﬁcant side effects. This includes non-cardiovascular effects (e.g. pulmonary ﬁbrosis and thyroid dysfunction with amiodarone), and of particular importance, the risk of life-threatening ventricular proarrhythmia including TdP in up to 5% of patients.19,20 Most of these antiarrhythmic drugs prevent or terminate AF by altering the function of potassium or sodium channels within the atrial cells. Blockade of potassium channels may prolong ventricular repolarization — and hence, the refractory period — resulting in QT-interval prolongation. Given the risk of severe proarrhythmia, the safety proﬁle of many current antiarrhythmic drugs is far from ideal.
From the early twentieth century, drug therapy has played an important role in the management of atrial arrhythmias. Quinidine was the ﬁrst antiarrhythmic used to successfully restore and maintain sinus rhythm in atrial ﬁbrillation (AF). Subsequently, a large number of other drugs have become available. Although the efﬁcacy of many of these agents is impressive, side effects are a frequent occurrence. Amongst the most worrying side effects are QT-interval prolongation and risk of proarrhythmia, including torsade de pointes (TdP)21
Flecainide, a class 1C anti-arrhythmic agent, depresses the rate of depolarization of cardiac action potentials producing a membrane stabilizing action. It is a very effective anti-arrhythmic agent against supraventricular arrhythmias, nevertheless flecainide is contraindicated in patients with structural heart disease because it increased mortality.22 The proarrhythmic effect of flecainide may be related to promoting a reentry in ventricular tissue. The phenomenon is due to a rate-dependent blockade of rapid sodium channels slowing phase 0 of depolarization and an inhibition of the slow calcium channel.23 In cases of overdose, the mortality with class Ic agents has been reported to approach 22%. Conduction disturbances began with widening of QRS complex which can rapidly progress to ventricular tachycardia, electromechanical dissociation and asystole.
Despite the large number of available antiarrhythmic agents, signiﬁcant QT-interval prolongation and risk of severe proarrhythmia, including torsade de pointes, limit pharmacological opportunities in the management of atrial arrhythmias. The risk of proarrhythmia has been demonstrated in class I and class III drugs, but signiﬁcant variability has been observed between agents of the same class. Electrophysiological drug effects found to be important in the etiology of proarrhythmia include QT- interval prolongation through selective blockade of the delayed rectifying potassium current (IKr), early afterdepolarizations, transmural dispersion of repolarization, and a reverse rate dependence. Interestingly, less proarrhythmic potential is seen or anticipated with agents that are able to block multiple ion channels and those with atrial selectivity, despite moderate QT prolongation. This observation has helped steer the development of newer drugs, with some promising preliminary results.