Cardiovascular Drugs and Therapy 1991;5:617-628 9 Kluwer Academic Publishers, Boston. Printed in U.S.A.

The Pharmacologic Treatment of Atrial Fibrillation Roberto Bolognesi Cattedra di Cardiologia, Universitd degli Studi di Parma, Parma, Italy

Summary. The pharmacologic treatment of atrial fibrillation (AF) is aimed at controlling the ventricular response, restoring sinus rhythm, and preventing or delaying relapses. In the control of ventricular response, digitalis maintains a primary role when the arrhythmia is accompanied by heart failure. In ischemic, hypertensive, and degenerative (whose number is increasing at present) cardiopathies without evident ventricular dilatation, treatments with calcium antagonists (such as verapamil, gallopamil, or diltiazem) or betablocking agents must be preferred. In order to control the ventricular response in patients with chronic AF during physical activity, the association of digitalis with beta-blocking agents or calcium antagonists seems to provide satisfactory results. The drugs of the IC class, especially flecainide, represent a certain therapeutical progress in the restoration of sinus rhythm in the treatment of paroxysmal atrial fibrillation affecting subjects without evident alterations of ventricular function, particularly in subjects with WolffParkinson-White syndrome, with forms of vagal origin, or with atrial fibrillation alone. A therapeutic combination of digitalis and quinidine may produce resolution of the arrhythmia in the presence of altered ventricular function or when AF is of an uncertain onset. In patients with hypertensive, ischemic, and/or degenerative cardiopathy without evident ventricular or advanced heart failure, the verapamilquinidine association may also be effective and even quicker. The combination of drugs of the I and III class for restoration of the sinus rhythm in particularly resistant forms of AF without evident structural heart alterations is promising but must be verified in a greater number of patients. In the prevention of relapses amiodarone appears to have the widest spectrum of advantages from an electrophysiologic point of view; however, because of its many side effects, amiodarone represents a late therapeutical choice. The promising results obtained with flecainide are disputed by the results of the CAST, which limit the possibilities of using this drug to a low number of cases (W.P.W. syndrome, AF of vagal origin, atrial fibrillation alone). In the past, quinidine and disopyramide have been the drugs most widely used in the prophylaxis of AF. These drugs have a similar efficacy, and both of them provided some positive results. However, because of untoward side effects (especially for quinidine) during chronic treatment, the use of these drugs has been questioned. Perhaps in the majority of patients, the less dangerous therapeutic choice after the termination of the fibrillation is a combination of drugs slowly down AV node activity (digitalis or calcium antagonists and beta blockers) with class IA antiarrhythmics. Cardiovasc Drugs Ther 1991;5:617-628 Key Words. atrial fibrillation, antiarrhythmic agents, quinidine, digitalis, amiodarone, calcium antagonists

A t r i a l fibrillation ( A F ) is a c o m m o n l y o b s e r v e d arr h y t h m i a [1-6], f r e q u e n t l y r e q u i r i n g medical t r e a t ment. The first a p p r o a c h is u s u a l l y pharmacologic, even though e x t e r n a l d i r e c t c u r r e n t shock (D-C) is believed to be more effective [7], since it can immediately t e r m i n a t e t h e a r r h y t h m i a ; D-C shock should be performed as first-line i n t e r v e n t i o n w h e n A F r e p r e sents a medical e m e r g e n c y [7], or it m i g h t be applied when pharmacologic t r e a t m e n t fails to r e s t o r e sinus r h y t h m . H o w e v e r , D-C shock is n o t a l w a y s well accepted by p a t i e n t s a n d m a y p r o d u c e some u n t o w a r d effects [8,9]; in addition, it c a n n o t be u s e d in all medical situations. The p u r p o s e s of t h e p h a r m a c o l o g i c t r e a t m e n t of A F are 1. To correct the u n d e r l y i n g disease ( h e a r t disease, h y p e r t h y r o i d i s m , g a s t r o e n t e r o l o g i c a l disease, electrolyte imbalance, acidosis, etc.). 2. To modify the u n d e r l y i n g electrophysiologic mechanisms t h a t m a i n t a i n t h e a r r h y t h m i a a n d t h e rapid rate of v e n t r i c u l a r r e s p o n s e . This r e v i e w will focus on t h i s l a t t e r clinical approach. Such pharmacologic t r e a t m e n t s of A F aim at a) slowing v e n t r i c u l a r r e s p o n s e , b) r e s t o r i n g sinus r h y t h m , and c) p r e v e n t i n g or d e l a y i n g relapses. Clinically A F m a y be classified as chronic, p a r o x y s m a l , and subacute. Chronic A F lasts m o r e t h a n 4 - 6 weeks [10,11]. P a r o x y s m a l A F is a n a c u t e t y p e of A F t h a t is accompanied b y some s u b j e c t i v e s y m p t o m s . I t r e c u r s f r e q u e n t l y a n d m a y lead to some d e g r e e of haemodynamic i m p a i r m e n t . S u b a c u t e A F can b e r e f e r r e d to as a type of a r r h y t h m i a of r e c e n t o n s e t w i t h o u t r e l e v a n t symptoms. The lack of s y m p t o m s is d u e to a s p o n t a n e ous or d r u g - i n d u c e d low v e n t r i c u l a r r a t e . S u b a c u t e A F tends to become chronic A F , a n d t h e i r differential diagnosis is often difficult. I n addition, t h e r e a r e some forms of A F t h a t occur u n p r e d i c t a b l y w i t h an acute

Address for correspondence and reprint requests: Dr. Roberto Bolognesi, Cattedra di Cardiologia, Clinica Medica Generale, Universita degli Studi, Via Gramsci 14, 43100 Parma, Italy. 6/7

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onset, usually last for a short time, and m a y recur spontaneously, also during the same day. These intermittent A F s are often unresponsive to therapy. The p r i m a r y objective of medical t r e a t m e n t varies in relation to the critical clinical pictures shown by the different forms of AF. F o r instance, the hemodynamic consequences of paroxysmal A F mainly require a t r e a t m e n t capable of rapidly reducing the ventricular response; in intermittent AF, the t r e a t m e n t should be aimed at preventing relapses. H o w e v e r , in all types of AF, the goal of the t r e a t m e n t is restoration of sinus rhythm. Institution of p r o m p t t r e a t m e n t in all cases of paroxysmal A F is still a m a t t e r of controversy. Many clinicians minimize the need of sinus r h y t h m restoration in acute AF because t h e y think t h a t the arrhythmia m a y spontaneously undergo remission (as often m a y happen), or at most, use a d r u g to decrease the ventricular response in the hope t h a t a reduction in heart r a t e m a y t e r m i n a t e (and it sometimes does) AF. Among the forms of paroxysmal A F that definitely need an immediate t r e a t m e n t are those occurring during an acute myocardial infarction or those complicating Wolff-Parkinson-White syndrome. Control of Ventricular

Response

It has been usually r e p o r t e d that controlled heart rate during A F must be maintained at r e s t in a range of 50-90 beats/min [12,13]. However, studying the optimal ventricular rate during A F by an aortic blood flow ultrasound technique, Rawles [14] found that a ventricular response of 90 beats/min at r e s t would result in an acceptable control with the least compromise of cardiac output. Digitalis The first drug that has been considered for this purpose is digitalis. E v e n long before the electrocardiographic era, Bouillaud [15] discovered that digitalis was able to decrease an irregular and frequent heart rate in cardiac patients. E v e n though we cannot be absolutely certain about the cases reported, they were probably mostly subjects with AF. Since then, this drug has been successfully employed in the t r e a t m e n t of A F and still maintains its p r e e m i n e n t role as a therapeutic agent for the control of this a r r h y t h m i a [16]. E v e n though various authors seem to agree that digitalis is suitable for the t r e a t m e n t of AF, one should question whether the broad and extensive use of this drug is still correct in this situation. Through an indirect vagomimetic and antiadrenergic action, digitalis [17-18] appears to be effective in controlling ventricular response, although in situations w h e r e ventricular response is v e r y high, the ef-

Table 1. Contraindications to digitalis and its questionable use in the treatment of atrial fibrillation

Wolff-Parkinson-White syndrome 9 Myocardial infarction 9 Hypertrophic obstructive cardiomyopathy 9 Bradycardia-tachycardia syndrome 9 Vagally induced atrial fibrillation a Recurrent AF for prophylaxis ~The essential feature of vagal origin atrial fibrillation is the occurrence of the attacks at night, at rest, or in digestive periods, rather than during the day or physical activity. The relationship between the autonomic nervous system (vagal hypertone) and the arrhytmia can be unmasked by Holter monitoring when the paroxysmal attack is preceded by a decrease in sinus nodal rate and by repeated atrial premature beats.

fect of digitalis m a y be mild [19]. In addition, its latency of action m a y sometimes be unsatisfactory [20]. In fibrillating patients with h e a r t failure, digitalis should be doubly useful. About half of the fibrillating patients are old [1-6] and have vulnerable hemodynamics [21]. Thus a h e a r t failure can easily lead to an uncontrolled A F when the a r r h y t h m i a itself is a side effect of an u p w a r d decompensation, since a systolic dysfunction occurs in about 50% of the patients [22]. Digitalis used in these conditions could magnify the hemodynamic as well as the electrophysiologic effects. H o w e v e r t h e r e are some situations in which the use of digitalis is harmful or questionable (Table 1). Undoubtedly, digitalis m u s t not be used w h e n A F arises in subjects showing W.P.W. syndrome, because its action on atrium, A V node, and accessory pathways would result in an increase of the ventricular response, which is already high [13,23]. Moreover, the use of digitalis in A F during the acute phase of myocardial infarction m a y be dangerous because it decreases the threshold of ventricular fibrillation [24]. Another situation in which the use of glycosides is not advisable is hypertrophic cardiomyopathy [25]; in this case, the hemodynamic effect of this d r u g m a y be more dangerous t h a n its favorable electrophysiologic action on the decrease of ventricular rate. Finally, in vagally induced A F , digitalis is contraindicated [26] because of its indirect vagomimetic and antiadrenergic effect that would maintain the a r r h y t h m i a .

Verapamil Given these limitations in the use of digitalis for the control of ventricular heart rate during AF, it a p p e a r s that alternative approaches are needed. In 1965, Bender et al. [27], using 5 m g of verapamil intravenously, observed a rapid decrease in the ventricular response of an atrial flutter t h a t arose postoperatively a f t e r the correction of an interatrial defect. The authors

Antiarrhythmic Agents and Atrial Fibrillation

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Table 2. Verapamil in the treatment of acute and chronic atrial fibrillation Preferential use

9 9 9 9

Hypertension Ischemic nondilated cardiopathy Hypertrophic cardiomyopathy Lung disease

To be used with caution

9 When given in a rapid IV bolus 9 In patients with low adrenergic tone 9 In patients treated with other calcium antagonists or vasodilator therapy in patients on class III antiarrythmic agents

Not to be used

9 Heart failure class IV patients 9 Patients who are already in therapy with beta blockers or disopyramide or propafenone 9 In patients with arterial pressure - 100 mmHg 9 In patients with bradycardia-tachycardia syndrome 9 In patients with Wolff-Parkinson-White syndrome

thought t h a t the drug used would act on betaadrenergic receptors. Since verapamil was not able to reduce isoproterenol-induced tachycardia, its proposed role as beta blocker was abandoned. Only later was it noted t h a t the slowing action of verapamil on the AV node was related to its action as a calcium antagonist. Following that early observation, several studies have confirmed the therapeutic effectiveness of verapamil. Its use in the t r e a t m e n t of A F with a high ventricular rate is worldwide [28-36]. Recently [37,38] we have employed v e r a p a m i l in 139 patients with A F of different etiologies. This d r u g has proven to be even more satisfactory than digitalis in the control of ventricular r a t e in patients with A F and coexisting hypertension, nondilated ischemic, or hypertensive cardiopathy and lung diseases. Verapamil has also been used by various authors [19,36] and by us [37,38] in the absence of m a j o r complications in subjects with h e a r t failure of N Y H A class 1 and 2. The occurrence of m a j o r side effects (severe hypotension and asystole [39,40] seems related to an inappropriate use of the d r u g in patients already on t r e a t m e n t with beta blockers and/or vasodilators or to its excessively rapid I V administration. Favorable effects of verapamil can be shown electrophysiologically by depression of the amplitude of action potentials in the upper and middle regions of the AV node and in lengthening the time-dependent AV nodal refractory period [41-43]. In addition, b y increasing the atrial rate causing the disorganization of atrial impulses that invades the u p p e r p a r t of AV node, verapamil reduces the ability of these impulses to cross the AV node; like digitalis, v e r a p a m i l is not recommended to control the ventricular r a t e in patients with both A F and coexisting preexcitation syndromes in

whom conduction occurs primarily t h r o u g h the accessory pathways [44,45] (Table 2). The use of verapamil is not the only alternative to digitalis, since the two drugs can be administered together because of their different sites of action on the AV node [19]. Thus, for some authors [46] this combination represents the t r e a t m e n t of choice in many patients with chronic AF.

Other calcium antagonists Gallopamil and diltiazem having essentially the same electrophysiologic characteristics as v e r a p a m i l induce similar effects in the control of ventricular r a t e during atrial fibrillation [20,47-49]. I n t r a v e n o u s diltiazem has been used in patients with advanced h e a r t failure without adverse effects [50,51], although f u r t h e r evaluation of this use is required. Beta-adrenergic blockade Beta blockers are also used to control ventricular response alone [52-55] or in combination with digitalis [56] when A F is sustained b y physical activity, an excess of beta-receptor stimulation, thyrotoxicosis, anesthesia with halothane and cycloproprane, and pheochromocytoma. During chronic t r e a t m e n t , attention m u s t be given to the intrinsic sympathomimetic activity of different beta-blocking agents [55-57]. Leclerq et al. [56], using 24-hour E K G monitoring in A F patients, recorded a reduction of mean heart r a t e throughout the day with propranolol, only during daytime with acebutolol, and an increase of mean heart r a t e during the night with pindolol. This last effect induced some authors [58] to consider pindolol in combination with digoxin the choice t r e a t m e n t for chronic AF. Nadolol seemed to be particularly effective in

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catecholamine-dependent atrial fibrillation arisin~ during physical activity or other stress [53,57]. Recently, esmolol, a new beta-blocking agent with a short time effect and a rapid elimination, has been utilized [59,60] during paroxysmal AF; its action has been proved at least as useful as verapamil [61], even though the brief half-life necessitates a maintenance infusion. In choosing beta blockers to control ventricular responses, one has to consider not only the type of AF and the underlying etiology, but also the pharmacodynamic properties of beta blockers, as well as their hemodynamic influences (in this regard, the vasodilating action of pindolol can be advantageous in certain situations).

Class I and class I I l antiarrhythmics In order to reduce ventricular response in AF both classes I and III of antiarrhythmic agents, directly depressing AV nodal conduction should be considered [62-64]. Unfortunately, through an indirect effect mediated via the autonomic neural system, most of the class I agents induce an indirect increase of ventricular rate [62-64]. Because of its direct electrophysiologic effect on AV node and its indirect antiadrenergic action, amiodarone might be successfully used alone in patients with nondilated hypertrophic or ischemic hearts, or in combination with digitalis in dilated cardiomyopathy [65]. Sick sinus syndrome Treatment of AF that represents the hyperkinetic expression of the tachycardia-bradycardia syndrome may represent a troublesome issue because such AF is paroxysmal. Most of the antiarrhythmic agents utilized to control the ventricular rate can cause further deterioration in a previous existing sick sinus nodal function [66]. Best control of this kind of AF may be obtained with the prophylatic implantation of a temporary pacemaker. Exercise and AF A common problem in the clinical practice is the optimization of ventricular rate in fibrillating patients who perform physical activity. Redfors [67] reported that the use of digitalis may produce some beneficial effects; moreover, these effects are partial, even when the dose of the drug is increased. Therefore the effect Of digitalis alone appears to be inadequate in the control of ventricular response, and thus the association of digitalis with calcium antagonists (verapamil, gallopamil, diltiazem), beta blockers [19], or amiodarone is required.

Wolff-Parkinson-White and A F When AF affects patients with W.P.W. syndrome, it is more important to control the arrhythmia or to prevent relapses than to control the ventricular response. The use of I class (subgroup C) drugs may be best [68].

Sinus Rhythm Restoration Restoration of sinus rhythm is the aim in the majority of patients with AF. In fact, AF is associated with a doubling of the incidence of mortality, regardless of the underlying cardiac condition [3,4,6]; furthermore, in patients with AF the risk of stroke is greater than in a control population [69]. The conversion of AF to sinus rhythm improves hemodynamic parameters and ameliorates various symptoms (such as disabling palpitations or dyspnea) accompanying AF, even when the ventricular response is under control [70,71]. Therefore, the maintenance of sinus rhythm is desirable. Age, type of underlying heart disease, duration of arrhythmia, left ventricular function, and left atrial size are the most important factors that influence a successful restoration of sinus rhythm in fibrillating patients [7,70,72,73]. Concerning heart disease, underlying AF, a significant reduction of an incidence of rheumatic valvular disease, and an increase of hypertensive, ischemic heart disease has been observed in recent years [21,74]. This changing pattern makes it difficult to evaluate and to compare the effects of the various antiarrhythmic agents. A long duration of arrhythmia should not be the unique reason why the restoration of sinus rhythm is not attempted. In fact, with pharmacologic treatment we have successfully cardioverted AF lasting several years in patients with previous thyroid illness [37,38,54,55]. Concerning left atrial enlargement, we found that sinus rhythm restoration was possible, even when atrial diameters were between 4 and 5.5 cm (echocardiographic evaluation). After normalization of the rhythm, a significant reduction of diameters (up to 0.5 cm) has been observed [74], confirming that atrial fibrillation contributes to atrial enlargement and thus maintains itself.

Digitalis for conversion to sinus rhythm Historically, in the 19th century digitalis was reported to be capable of regularizing and decreasing irregular and frequent heart rate in patients with cardiac disease [15]. Now, while it is generally accepted that digitalis can be used to control the ventricular response, its use to restore sinus nodal rhythm is still a matter of controversy.

Antiarrhythmic Agents and Atrial Fibrillation

In spite of the fact that Pick [75] attributed a direct converting effect on atrium to digitalis, most authors [76-78] believe that if digitalis promotes reversion to sinus rhythm, this depends on ventricular slowing and overall hemodynamic improvement. On the other hand, Friedberg [79] states that AF termination during digitalis therapy may be purely coincidental. Other authors [80,81] suggest that digitalis tends to perpetuate the acute attack of AF because of its direct profibrillatory effect on the atrium. All these discrepancies in the interpretation of the results of digitalis therapy must be at least in part attributed to the multifactorial actions of glycosides on cardiac cell membrane, autonomic and central nervous system, baroceptor sensitivity, coronary and peripheral vasculature contractility, and ventricular rate [82]. In addition, Jogestrand [83] demonstrated that the atrial concentration of digoxin was significantly higher in patients with AF than in those with sinus rhythm. The most common electrophysiologic effect of digitalis on atrial fibers is a shortening of the refractory period [80,81,84], a phenomenon known to maintain AF. In spite of this, Weiner et al. [85] reported successful cardioversion in 85% of 45 subjects with paroxysmal AF treated with rapid digitalization, although there was no indication of the severity of AF. Digitalis should not be considered as a first-line therapy in sinus node rhythm restoration; however, in fibrillating patients treated with digitalis to control ventricular response, sinus rhythm may be restored by the subsequent administration of quinidine [86,87]. This is the most common therapeutic procedure used, especially by internists in clinical practice, to restore sinus rhythm. Calcium antagonists and beta blockers In a low percentage of cases (5-13%) [31,37,38,63,88] conversion to sinus rhythm may be accomplished with calcium antagonists (verapamil, gallopamil, diltiazem) or beta-blocker treatment, probably as a result of their effect in controlling the ventricular response and/or in producing a significant hemodynamic improvement (Table 3). The majority of patients who we converted with the administration of verapamil suffered from hypertension or from hypertrophic and/or ischemic nondilated hearts [37,38]. Franchi et al. [89] found that, from an electrophysiologic point of view, verapamil may present some cardioverting effects, because it reduces the dispersion of the functional refractory period of atrial cells in ischemic patients. This electrophysiologic effect has been questioned by Shenasa et al. [90], who showed

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Table 3. Reversion to sinus rhythm after treatment with various antiarrhythmic agents given alone or in combination in patients with paroxysmal or recent onset atrial fibrillation Drugs

Successful %

References

Digitalis Quinidine + digitalis Procainamide

20-85 70-88 40-43 79 10-16 6.5-17 16 64 30-75 61-92 45 50-92

85,87 8,87 87,72 87 31,38,63 82,88 53,97 65 97 74,82,104 97,98 38,82,122,125

Ajmalina

Verapamil Diltiazem Beta blockers Amiodarone Disopyramide Flecainide Propafenone Verapamil + quinidine

that verapamil caused a prolongation of arrhythmia in both spontaneous and electrically induced AF. The use of beta-blocking agents may be successful when associated with quinidine in order to restore sinus rhythm [91-93]. Proto and Levi [94] reported restoration of sinus rhythm in 61% out of 233 patients with chronic AF, using quinidine in combination with various beta blockers. In addition, our and other groups found that the association of beta blockers with quinidine may result in a lower inotropic effect than either beta blockers alone or quinidine alone [95,96]. Other agents including flecainide At present, various potent antiarrhythmic drugs are available to improve or regularize the electrophysiologic properties of the atrium [63,64]; therefore, sometimes AF may be treated as other supraventricular hyperkinetic arrhythmias (i.e., as alteration of the rhythm to be rapidly reversed). Among these the most widely used antiarrhythmic agents are disopyramide [97], propafenone [98,99], amiodarone [65], and flecainide [100]. The most promising results in the treatment of paroxysmal AF are those obtained with flecainide (Table 3). Both intravenous and oral flecainide have been shown to be effective and rapid in restoring sinus rhythm during paroxysmal AF in various common clinical situations [101-104]. Our experience is in agreement with these observations [74]. Flecainide has also been reported to convert AF developing after cardiosurgical operations [105] and vagaUy induced paroxysmal AF [106,107] to sinus rhythm, whereas it appeared to be ineffective in the treatment of chronic AF [108]. Unfortunately, even though flecainide has beneficial effects on paroxysmal AF, the use of this drug has been questioned because of the surprising results

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of the CAST [109]. This study indicates that subjects with ischemic cardiopathy and depressed ventricular function have a worse prognosis when treated with flecainide, probably because this drug favors ventricular arrhythmias. This side effect restricts the use of this drug, even in the case of supraventricular arrhythmias. The use of flecainide must also be limited in patients with dilated myocardiopathy and severely decreased ventricular function. T r e a t m e n t with flecainide in patients affected by ischemic or dilated cardiomyopathy without severe depression of ventricular function does not seem to be excluded, even though it is reasonable to use amiodarone first because of its antiarrhythmic properties associated with coronary dilating and antiadrenergic activities [65]. Sihm et al. [110] r e p o r t e d severe arrhythmic side effects (four hypokinetic and five hyperkinetic arrhythmias with one decease) in 9 out of 100 fibrillating patients without heart failure t r e a t e d with flecainide. These patients were old and were affected by ischemic cardiopathy and/or p r e s e n t e d widened basal QRS. Because of these side effects, the authors argue against the use of flecainide in any type of arrhythmia. There are patients with r e c u r r e n t episodes of paroxysmal A F without evidence of underlying structural alterations of the heart; in these subjects, flecainide appears to have positive effects, and at the present time no relevant [111] or sporadic [112] untoward side effects have been described. The treatment of A F with amiodarone represents a valid alternative to fiecainide. Amiodarone may be a first-choice drug in the t r e a t m e n t of A F in patients affected by dilated myocardiopathy or ischemic heart disease without severe alterations of ventricular function [65]. In a series of patients who underwent heart surgery and subsequently developed AF, IV amiodarone was successfully administered in our clinic to obtain a rapid restoration of sinus r h y t h m (unpublished observations). Coumel et al. suggest the use of either flecainide or amiodarone, alone or in combination, for convertion of vagally induced paroxysmal A F [106,107,113]. Propafenone and disopyramide might be considered a second-line therapy for reversion to sinus rhythm of AF.

Wolff-Parkinson-White sgndrome A particular attention must be focused on the treatment of AF during W.P.W. syndrome. AF seems to be more frequent in this disease and is a particularly dangerous condition, because it might produce ventricular fibrillation [114]. Cardiologists need to know the lowest RR interval during A F in these patients, because values lower than 205 ms indicate a certain

Table 4. Sinus rhythm restoration after treatment with various antiarrhythmic agents given alone or in combination in patients with chronic atrial fibrillation

Drugs

Successful %

References

Quinidine Digitalis + quinidine Amiodarone Amiodarone + digitalis Amiodarone + quinidine Diosopyramide Beta blocker + quinidine Verapamil + quinidine

62 50-90 53-65 50 94 43-76 61 60-84

Procainamide

57

119 10 63-65 65 65 97,124 94 37,38,82, 120,121,124 118

risk [ 115]. When the W.P.W. syndrome is complicated by AF, both control of ventricular response and restoration of sinus r h y t h m must be pursued simultaneously. The antiarrhythmics class I (subgroup C) seem to be particularly useful for this purpose [68]. Data in the literature argue in favor of flecainide [115,116]. In addition, propafenone and ajmaline also have an indication in this type of A F [23], because t h e y may be given intravenously [68]. The HV interval may critically lengthen during the administration of these drugs in subjects with a latent disturbance of the His Purkinje system and thus a careful examination of ECG is necessary (risk of advanced AV distal block). More consistent lengthening of the H V interval has been found during the use of ajmaline [117].

Cardioversian Cardioversion is difficult to obtain in long-lasting A F or in A F of uncertain onset, which sometime becomes chronic [21,118]. In the case of long-lasting AF, antiarrhythmic agents are generally used in association to restore sinus r h y t h m (Table 4). Similarly, pharmacologic association might be effective in subjects affected by paroxysmal A F who did not respond to cardioversion alone. Among the antiarrhythmie drugs utilized in these associations, quinidine plays a key role [62,63,119]. Unfortunately, the use of this drug alone is limited because of its pharmacokinetics and vagolytic effects [63].

Drug combinations Digitalis and beta blockers are the more commonly used drugs in association with quinidine. The combination of quinidine and digitalis is probably most common in Italy [86]. We found the combination of quinidine and verapamil [37,38] as useful as the above-described combi-

Antiarrhythmic Agents and Atrial Fibrillation

nation of quinidine with digitalis [120-125]. If the specific dosage, timing, and route of administration of verapamil and quinidine are carefully monitored to avoid the occasionally described severe hypotension and/or sinus or atrioventricular blocks [40,126], the use of this combination is safe. Since verapamil is capable of producing a rapid slowing down of the ventricular response during AF, the association of verapamil and quinidine appears to be more advantageous than the digitalis plus quinidine combination because of its rapid effect on sinus rhythm restoration. In particular, we have found the quinidine plus verapamil association in fibrillating patients with hypertension and/or hypertensive or ischemic cardiopathy to be very effective [37,38]. Epstein and Rosing reported [126] that when oral verapamil was administered in association with oral quinidine, a serious hypotension may develop; however, in their three cases the reported patients had severe hypertrophic myocardiopathy, a disease characterized by marked sensitivity to vasodilation, which can be produced by verapamil in combination with quinidine [39]. Since gallopamil [46] and diltiazem [127,128] appear to be similar to verapamil from an electrophysiologic point of view, a combination of diltiazem and quinidine might be successfully utilized for AF conversion. This hypothesis requires clinical studies to be verified. The combination of amiodarone and digitalis has been used, but it gave a partial and delayed success in the treatment of chronic AF [129-131]. The association of class I and III antiarrhythmic agents has been employed in refractory forms of chronic AF [65,132]. Amiodarone-flecainide has been used in the treatment of advanced AF of vagal origin [107]. However, the side effects of these combinations must be carefully evaluated.

Drug Prophylaxis of Atrial Fibrillation A successful drug prophylaxis of AF is an important clinical aim because of the many adverse effects of arrhythmia; prevention is particularly indicated when arrhythmia is accompanied by severe complications or when clinical arrhythmias occur at short intervals [3,6,69-71,133,134]. Maintenance of sinus rhythm depends on various factors, including the type of the underlying disease, the duration of the last AF episode, the size and function of heart chambers, structural and functional abnormalities of the sinus node, neural atrial disease, fibrosis of the atrial myocardium, the patient's age, and other factors [134-139]. There are no studies that take all of these factors into account. Thus, no general

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consensus exists as to the value of a certain drug. Prophylaxis of AF therefore reflects personal interpretation of the reported clinical experience. Nonetheless, in a review of drug prophylaxis of AF, Campbell [134] reported that quinidine and its derivatives were effective in AF prophylaxis, but the need for drug withdrawal due to side effects [140,141] was frequent. A meta-analysis [135] of randomized control trials published between 1970 and 1984 shows that quinidine treatment is more effective than no suppressive antiarrhythmic therapy in keeping patients in sinus rhythm. However, this therapy is associated with at least 3% annual incidence of mortality (three times more than in untreated groups) [135]. Campbell believes that in individual clinical situations, disopyramide may be less dangerous and as effective as quinidine [134]. This opinion arises from a double-blind controlled study of Haertel et al. [142], in which disopyramide was more effective than a placebo and as effective as quinidine in preventing AF relapses; however, another study [143] comparing the relative efficacy of quinidine, disopyramide, and a placebo at 6 months after AF cardioversion did not show significant difference among the three groups in the number of patients maintaining sinus rhythm. Digitalis itself, when given prophylactically, does not prevent relapses, but it can cause longer paroxysmal attacks, a result consistent with its action in reducing the atrial refractory period [144]. From an electrophysiologic point of view, amiodarone seems to be the most effective drug in the prevention of AF [65,145]. Oral amiodarone has been reported [97] to maintain sinus rhythm in about 80% of patients after 3 months from conversion to sinus rhythm. The outcome of amiodarone prophylaxis does not seem to be influenced by the duration of the last AF episode, the type of underlying heart disease, the patient's age, or left ventricular dysfunction [65,145]. Indeed, the importance of left atrial dilatation in determining the outcome of amiodarone prophylaxis has been disputed [137,138,145]. Unfortunately, in longterm therapies, as for the maintenance of sinus rhythm, doses of amiodarone higher than 1000 mg/ week may lead to several serious side effects and subsequent unavoidable drug withdrawal [146-152]. There are promising preliminary data [153-155] on the efficacy offlecainide in the prevention of AF recurrences. Flecainide might be administered as prophylaxis in patients without relevant underlying cardiopathies; an elective indication is represented by the cases of AF complicating the W.P.W. syndrome [68] or by AF forms of vagal origin [106]. However, there are a growing number of reports concerning the ad-

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verse effects of Class IC agents in long-term administration [156-159]. These data tend to restrict the use of flecainide and other Class IC drugs in the prevention of paroxysmal attacks. In 109 patients with recurrent episodes of symptomatic AF, treated with propafenone and subsequently with sotalol, Antman et al. recently found that 39% of patients on propafenone and 50% of patients on sotalol were free of symptomatic relapses at 6 months from their last AF [160]. Although the results of this study may appear encouraging, further evaluation seems necessary to define the overall effects of these newer antiarrhythmic agents [153-162]. At present the overall results of the effectiveness of antiarrhythmic agents in the prevention of AF relapses are unsatisfactory. The pharmacologic side effects described during long-term therapy with antiarrhythmic agents make this problem more striking; thus drug prophylaxis of AF is still an aim to be reached.

In preventing A F relapses the following therapeutical approaches could be proposed: In fibrillating pa-

tients without underlying overt heart disease, the use of newer antiarrhythmic agents should be encouraged; in subjects with hypertension or hypertensive and/or ischemic heart disease, the association of verapamil with quinidine may be advantageous. On the other hand, if the left ventricle is dilated or systolic left ventricular performance is depressed, digitalis in combination with class IA antiarrhythmic drugs might be considered safer.

Conclusion In patients with AF, no therapeutic approach is universally applicable. In the presence of left ventricular systolic failure, both paroxysmal AF and chronic AF have been successfully treated with digitalis. If AF is a consequence of hypertension or ischemic heart disease (without an overt left ventricle enlargement) calcium antagonists (such as verapamil, gallopamil, diltiazem) or beta blockers must be considered, because the electrophysiologic and hemodynamic effects of these drugs seem to produce satisfactory results. Treatment of paroxysmal AF with class IC drugs or with amiodarone often produces a high percentage of rapid restoration of sinus rhythm; however, these drugs are contraindicated when arrhythmia develops in patients with depressed left ventricular function. In contrast, amiodarone is indicated in a wider number of patients, even though in our experience this drug appeared to be slightly less effective in sinus rhythm restoration. The use of digitalis in cardioverting patients with paroxysmal AF to sinus rhythm may pro-

vide some good results, but it is of second choice. Usually, in long-lasting AF sinus rhythm may be restored with an association of drugs, of which quinidine is still the key in terms of efficacy. Quinidine may be associated with digitalis, calcium antagonists, beta blockers, or (with caution) antiarrhythmic agents of class III. Digitalis does not prevent AF relapses, but rather it extends the duration of paroxysmal attacks. At present, from an electrophysiologic standpoint, amiodarone represents the most useful drug to maintain sinus rhythm after the end of the fibrillation. However, a series of side effects in a long-term treatment with amiodarone makes its use questionable. The promising results obtained with flecainide in AF prevention must be considered against the results of the CAST study, even though in AF complicated by W.P.W. syndrome or in AF of vagal origin flecainide administration appears to be effective and useful. The effects of propafenone and sotalol in AF prophylaxis are still under evaluation. Thus, in this condition the use of a drug controlling ventricular rate (digitalis, calcium antagonist, or beta blocker in relation to left ventricular function) in combination with a class IA antiarrhythmic agent might represent the safer therapeutical approach. References 1. Selzer A. Atrial fibrillation revisited. N Engl J Med 1982;306:1044-1045. 2. Ostrander LD Jr., Brandt RL, Kjelsberg MD, Epstein FH. Eelctrocardiographic findings among the adult population of a total natural community. Tecumseh, Michigan. Circulation 1965;31:888-898. 3. Kannel WB, Abbott RD, Savage DD, McNamara PM. Epidemiologic features of chronic atrial fibrillation. The Framingham Study. N Engl J Med 1982;36:1018-1022. 4. Petersen P, Godtfredsen J. Atrial fibrillation. A review of course and prognosis. Acta Med Scand 1984;216:5-9. 5. Campbell A, Caird FI, Jackson TFM. Prevalence of abnormalities of electrocardiogram in old people. Br Heart J 1974;36:1005-1011. 6. Kulbertus HE, De Leval-Rutten F, Bartsch P, Petit JM. Atrial fibrillation in elderly ambulatory patients. In: Kulbertus HE, Olsson SB, Schlepper M, eds. Atrial fibrillation. Molndal, Sweden: AB Hassle, 1982:148-157. 7. De Silva RA, Lown B. Cardioversion for atrial fibrillation. Indications and complications. In: Kulbertus HE, Olsson SB, Schlepper M, eds. Atrial fibrillation. Molndal, Sweden: AB Hassle, 1982:231-239. 8. Katz AM. Disorders of cardiac rhythm. Focus on disopyramide. Auckland: ADIS, 1986:143. 9. Resnekov L. High-energy electrical current in the management of cardiac dysrhythmias. In: Mandel WJ, ed. Cardiac arrhythmias. Philadelphia: J.B. Lippincott, 1980: 589-604. 10. Hurst JW, Paulk EA Jr., Proctor HD, Schlant RG. Management of patients with atrial fibrillation. A m J Med 1964;37:728-741.

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