REVIEWS

Proarrhythmia in Patients Treated for Atrial Fibrillation or Flutter Rodney H. Falk, MD

• Objective: To review data on the type, mechanism, and prevalence of the proarrhythmic effect of drugs used to treat atrial fibrillation or flutter. • Data Sources: English-language literature from the early 1960s to the present was identified by manual search of the literature; relevant articles were reviewed. Pertinent earlier studies were identified from references in the articles reviewed and were included when relevant. • Study Selection: All studies, controlled and uncontrolled, as well as individual case reports that contained data convincingly linking atrial antiarrhythmic therapy to a proarrhythmic side effect were included. • Data Extraction: Key data were extracted from each article in studies in which a causal relationship between the use of a drug and a proarrhythmic response appeared likely. • Data Synthesis: Antiarrhythmic therapy aimed at stabilizing the atrium may have adverse effects on the ventricle including torsade de pointes and, less commonly, sustained ventricular tachycardia. Different antiarrhythmic agents appear to have differing potentials for this proarrhythmic response, which is most common with class 1A agents. Other proarrhythmic responses to atrial antiarrhythmic agents include the acceleration of the ventricular response either by enhancing atrioventricular nodal or bypass tract conduction or by converting atrial fibrillation to flutter with 1:1 conduction. Calcium-channel blocking agents and, less commonly, digoxin may perpetuate the duration of paroxysmal atrial fibrillation, and virtually all agents can cause sinus node dysfunction or atrioventricular block. • Conclusions: Although drug therapy for atrial fibrillation or flutter is generally well tolerated, the potential exists for uncommon but serious proarrhythmic effects. Knowledge of the risk factors and symptoms of these adverse reactions will help to further reduce this risk.

Antiarrhythmic drugs may occasionally provoke a new arrhythmia or worsening of a preexisting arrhythmia—a phenomenon termed proarrhythmia (1-5). The earliest reports of drug-induced ventricular tachycardia were in patients treated for atrial fibrillation (6-8). Most recent studies, however, have concentrated on the incidence and mechanisms of proarrhythmia in patients prescribed drugs for the treatment of ventricular arrhythmias. Less attention has been paid to arrhythmic events in patients treated for supraventricular arrhythmias. Generally, these patients are considered to be at low risk for arrhythmia aggravation by antiarrhythmic agents, possibly because they often have minimal or no structural heart disease and rarely have concomitant ventricular arrhythmia. A distinction should be made between patients treated for re-entrant atrioventricular (AV) nodal or AV tachycardia and those treated for atrial flutter or fibrillation. In the former group, structural abnormality of the heart (other than the electrophysiologic abnormality) is uncommon, whereas patients with atrial fibrillation or flutter frequently have underlying heart disease and, consequently, may be at greater risk for adverse cardiac effects of antiarrhythmic agents. Many drugs are used to terminate or prevent atrial arrhythmias, although only quinidine and flecainide are officially approved by the U.S. Food and Drug Administration for this indication. In addition to drugs used to suppress supraventricular arrhythmias, other agents, including digoxin, beta-blockers, and certain calciumchannel blockers are useful in controlling the ventricular response to acute or chronic atrialfibrillation.These drugs may also have adverse effects on cardiac rhythm. I examine the occurrence and risk for proarrhythmia in patients with atrial fibrillation and flutter who are treated with antiarrhythmic or ventricular rate-slowing

Drugs Brand Name Duraquin, Quinidex Norpace Procan, Pronestyl Lanoxin Calan, Isoptin Cardizem Tamborocar Indocin Xylocaine Enkaid Cordarone

Generic Name quinidine disopyramine procainamide digoxin verapamil diltiazem flecainide propranolol lidocaine encainide amiodarone Annals of Internal Medicine. 1992;117:141-150. From Boston City Hospital, Boston, Massachusetts. For the current author address, see end of text.

AV WPW

Abbreviations atrioventricular Wolff-Parkinson-White © 1992 American College of Physicians

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Table 1. Proarrhythmic Effects of Agents Used for Treating Atrial Fibrillation or Flutter Adverse Effect Torsade de pointes

Quinidine (15), disopyramide (19), procainamide (20, 21), sotalol (25, 26)

Monomorphic ventricular tachycardia or ventricular fibrillation

All anti-arrhythmics implicated

Increased frequency or duration of paroxysmal atrial fibrillation or flutter

Digoxin (62), verapamil (64-67), diltiazem (67)

enhanced AV nodal conduction, decreased atrial rate or conversion of fibrillation to flutter

Comments

Agents Most Commonly Causing Adverse Effect

(43), flecainide (53), propafenone (52), lidocaine (48)

Acceleration of ventricular rate in the WPW syndrome with atrial fibrillation

Verapamil (71-73), digoxin (81), lidocaine (85), propranolol (83)

Aggravation of sinus node disease in the tachycardia-bradycardia syndrome

Virtually all antiarrhythmic agents including digoxin (98), calcium-blockers (96), and beta-blockers (96) in susceptible patients

High-degree AV block

Digoxin Type IA or IC agents

Aberrant ventricular conduction

Flecainide (57), propafenone (58)

Almost all antiarrhythmic agents can cause torsade but it is most common with IA agents and sotalol. Hypokalemia and bradycardia are precipitating factors. Risk of 1% to 2% in patients prescribed quinidine (fatal in 0.5% to 1%). Rare unless significant ventricular dysfunction present. Risk factors same as those for ventricular tachycardia in patients treated for ventricular arrhythmias (4, 5) Prevalence unknown. Clinical significance depends on severity of symptoms during atrial arrhythmia. Increase in rate may be associated with aberrant conduction or hemodynamic compromise or both. Flutter with 1:1 conduction may occur in 1% to 2% of patients treated for atrial fibrillation or flutter with IC agents, many of whom will develop significant symptoms. Intravenous drug most commonly involved. Verapamil and digoxin may cause life-threatening arrhythmias. Lidocaine and propranolol have been associated with increased ventricular rate, but this is very rare. Tends to occur at the offset of a paroxysm of atrial arrhythmia. Suspect in a patient with paroxysmal atrial fibrillation and worsening or new dizziness with drug therapy. Prevalence varies with drug and severity of sinus node disease. Uncommon complication. Generally occurs in patients with severe AV nodal or infra-His conduction system disease. May be life-threatening if complete block occurs. Main significance is difficulty differentiating atrial flutter from ventricular tachycardia. Aberration is most frequently tachycardia related.

* AV = atrioventricular; WPW = Wolff-Parkinson-White.

agents. The term proarrhythmia is used broadly, to include not only the provocation of ventricular arrhythmia but also the adverse effects on the atrium, AV node, and specialized conduction system. Each type of proarrhythmia is examined separately with a review of its prevalence and of the associated factors that may make proarrhythmic responses more likely. These proarrhythmic responses are summarized in Table 1.

the electrophysiologic properties of the ventricle and allowing the emergence of a new or worsened ventricular arrhythmia or by producing an increased ventricular rate that results in ventricular arrhythmia provocation.

Ventricular Arrhythmias in Patients with Atrial Fibrillation or Flutter

Polymorphic ventricular tachycardia associated with QT prolongation (torsade de pointes) is perhaps the most widely recognized arrhythmia associated with treatment of atrial fibrillation (9). Unlike monomorphic ventricular tachycardia, torsade de pointes is not uncommon in patients with a normal or near-normal ventricle although it probably occurs more frequently when underlying heart disease is present. Virtually all antiarrhythmic agents have been reported to cause torsade, but the arrhythmia is most commonly associated with type IA antiarrhythmics such as quinidine, procainamide, and disopyramide. Because quinidine is the most frequently prescribed drug for the prevention of atrial fibrillation in the United States, the risks for torsade with this drug are best known.

The cause of ventricular arrhythmias in patients with atrial fibrillation or flutter is multifactorial (Table 2). In persons with organic heart disease (for example, cardiomyopathy or ischemic heart disease), atrial and ventricular arrhythmias may be independent, unrelated manifestations of the same disease process. In contrast, in patients with the Wolff-Parkinson-White (WPW) syndrome and normal ventricular function, ventricular fibrillation may be provoked by rapidly conducted atrial fibrillation through a bypass tract with a short refractory period. In either situation, pharmacologic treatment aimed at controlling the atrial arrhythmia may, occasionally, adversely affect the ventricle either by altering 142

Torsade de Pointes

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Quinidine The earliest reports of ventricular arrhythmia provoked by quinidine occurred 70 years ago in a patient treated for atrialfibrillation(6), although it is not clear from the illustration accompanying that report whether this was truly due to torsade. In 1964, Selzer and Wray first accurately described quinidine-induced torsade (8). Their report coincided with the clinical introduction of electrical cardioversion for atrial flutter and fibrillation (10, 11) and, along with it, the widespread use of quinidine for postcardioversion prophylaxis. An early, nonrandomized British study of quinidine prophylaxis after electrical cardioversion for atrial fibrillation raised questions about the safety of the drug (12). Among 34 patients receiving quinidine, two patients died and one new episode of sustained ventricular tachycardia occurred. In comparison, no deaths occurred in a group of 85 patients who received no prophylactic therapy. As a result of these events, the trial was prematurely terminated and quinidine prophylaxis rapidly fell into disfavor in the United Kingdom (13). In contrast to the practice in the United Kingdom, quinidine is still used in the United States for prophylaxis of atrialfibrillation,but a recently published study raised concerns about the drug's safety (14). In a metaanalysis of six randomized controlled trials of quinidine prophylaxis conducted between 1970 and 1984, Coplen and colleagues found an unadjusted total mortality rate of 2.9% for quinidine-treated patients (12 of 413) compared with 0.8% (3 of 387) in the control groups—a threefold increase. It is important to note, however, that these figures represent all modes of death and that the precise cause of death was documented in only 7 of the 12 quinidine-treated patients, only three of which were sudden. Thus, it is possible that much of quinidine's apparent association with excess mortality was coincidental and was related to its use in sicker patients. If one assumes that all sudden deaths were caused by ventricular arrhythmia, the overall prevalence of malignant arrhythmia in the quinidine group (including an additional two nonfatal cardiac arrests) was 1.2% (1.5% if an unclassified death was arrhythmic) compared with 0% (or 0.25%) in the control group. Although review of Coplen and colleagues' data indicates an excess sudden-death rate in the quinidine group, no data were recorded about predisposing factors that, with careful modern management, might have been avoided. Quinidine-induced torsade has a number of such predisposing factors (14). Roden and colleagues (15) reviewed 20 cases of quinidine-induced torsade and noted that the arrhythmia occurred within 48 hours of starting quinidine treatment in most patients although four patients had been receiving the therapy for more than 1 year. Several risk factors for the development of the arrhythmia were identified, specifically a low serum potassium level and excessive bradycardia. Two thirds of the patients had a serum potassium less than 4.0 mmol/L, and Hypomagnesemia was present in one third of the cases in which the electrolyte was measured. A clear-cut complicating feature was present in all four patients who developed torsade after more than 1 year of therapy: hypokalemia in three and AV block in the fourth. Six of eight patients receiving quinidine for atrial

fibrillation developed torsade only after conversion of atrialfibrillationto sinus rhythm; the basic rhythm before torsade was unknown in two. Based on their overall clinical experience with quinidine, the authors estimated a minimum annual risk for the development of torsade de pointes of 1.5%. The development of torsade only after reversion from atrialfibrillationto sinus rhythm is well recognized and is probably related to a fall in ventricular rate. In susceptible hearts, bradycardia may be associated with the abnormal cellular phenomenon of early afterdepolarizations, which may be related to the development of torsade de pointes (16). Additional features that may induce or aggravate early after depolarizations are hypokalemia and low-dose quinidine. Quinidine-induced torsade is not dose related, and it has even been suggested that low serum levels of the drug may be more likely to provoke torsade than higher levels (17). Although quinidine-induced torsade is almost invariably associated with marked QT prolongation on the 12-lead electrocardiogram (ECG), the converse is not true; QT prolongation does not necessarily contraindicate continuation of the drug. Careful attention must be paid to serum levels of potassium in patients receiving quinidine, and every attempt should be made to maintain the potassium level at or above 4 mmol/L. Procainamide and Disopyramide Both procainamide and disopyramide are effective for preventing atrialfibrillationand both have been associated with the provocation of torsade (18, 19), but no study has attempted to systematically determine the prevalence of torsade with these drugs. As with quinidine-induced torsade, hypokalemia is considered to be a major precipitating factor (18, 20, 21). Although quinidine-associated torsade is not related to drug levels and may occur at subtherapeutic doses, it has been suggested that procainamide-induced torsade may be more common in patients with elevated levels of JV-acetylprocainamide, the first metabolite of procainamide (20, 21). Other Agents Many of the antiarrhythmic agents less commonly used in the United States to maintain sinus rhythm in patients with previous atrialfibrillationhave been occasionally implicated in the genesis of torsade. These inTable 2. Causes of Ventricular Arrhythmias in Patients with Atrial Fibrillation or Flutter Independent ventricular arrhythmias secondary to a common underlying disease process. Torsade de pointes precipitated by antiarrhythmic treatment of atrial fibrillation. Monomorphic ventricular tachycardia in a diseased ventricle with or without previous stable ventricular arrhythmia precipitated by antiarrhythmic treatment of atrial fibrillation. Rapid, preexcited ventricular response to atrial fibrillation in the WPW syndrome degenerating into ventricular fibrillation in an untreated patient with the WPW syndrome.* Provocation, or aggravation, of preexcited atrial fibrillation in the WPW syndrome by drugs used to control atrioventricular reentrant tachycardia or the ventricular response to atrial fibrillation. * WPW - Wolff-Parkinson-White.

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elude amiodarone (22, 23), which has also been used successfully to suppress torsade (9). The arrhythmia is said to be very uncommon with the IC agents, which have minimal effects on the QT interval (24). Sotalol Sotalol is a class III agent with beta-blocking properties. It is currently undergoing investigation in the United States for treatment of both atrial and ventricular arrhythmias and is used clinically in Canada. Several reports have documented the risk for torsade with this agent (25-28). Unlike the QT prolongation seen with quinidine that may be prominent at low serum levels, QT prolongation caused by sotalol is primarily concentration-dependent (27), and sotalol overdose is commonly complicated by torsade (26). The incidence of sotalol-induced torsade ranges from approximately 1% in patients receiving doses of 160 to 240 mg daily (28) to 5% to 7% in patients receiving 480 to 640 mg per day (data on file, Bristol-Myers-Squibb). As with the type IA agents, sotalol-induced torsade is aggravated by hypokalemia, and the combination of sotalol with a diuretic in a single tablet was implicated as a serious risk factor for this arrhythmia in patients receiving therapy for hypertension (25). The beta-blocking properties of sotalol may further increase the risk for torsade in susceptible patients by producing a relative or absolute bradycardia.

Monomorphic Ventricular Tachycardia and Fibrillation Patients with atrialfibrillationassociated with ventricular dysfunction may have concomitant ventricular arrhythmia, and provocation of sustained ventricular arrhythmia by drug treatment of atrialfibrillationis most probably a function of the underlying ventricular disease. Reports of drug-induced ventricular tachycardia orfibrillationin patients treated for atrialfibrillationare rare, presumably because many series exclude patients with clinically significant ventricular dysfunction. The type IC agents, which have been implicated in causing an increased risk for sudden death when used after myocardial infarction, have generally had a good safety profile for the treatment of atrialfibrillation(2931). However, a small series of cases suggested that, in the setting of chronic atrial fibrillation, the use of flecainide may cause life-threatening, wide-complex tachycardia during vigorous exertion even in patients without clinically significant ventricular dysfunction (32). A similar event has been reported in a patient with previous myocardial infarction receiving flecainide for paroxysmal atrial fibrillation (33). In these cases it is hypothesized that the rapid and irregular ventricular rate during atrial fibrillation, combined with both the use-dependent properties of the IC agents and the high levels of circulating catecholamines during exercise, may have resulted in enough inhomogeneity of conduction in a minimally diseased ventricle to produce a substrate suitable for sustained ventricular arrhythmia (32, 34, 35). 144

Drug-induced Acceleration of Ventricular Response during Atrial Fibrillation or Flutter The ventricular response to atrialfibrillationor flutter is determined by the refractory period of the AV node, the degree of concealed conduction within the node, and the level of autonomic tone. Alterations of one or more of these factors by antiarrhythmic agents, or the conversion of fibrillation to flutter, may result in an increased ventricular rate that may occasionally be dramatic and be associated with adverse hemodynamic consequences. Several drugs have been associated with this phenomenon. Quinidine Quinidine-induced ventricular rate acceleration in patients with atrialflutterhas been known for many years. The recognition of this potentially hazardous effect led, almost 50 years ago, to the recommendation to use digitalis glycosides concomitantly with quinidine to increase AV nodal block (36, 37). The use of digoxin in conjunction with quinidine therapy, however, is not a guarantee against 1:1 AV nodal conduction, which, rarely, may be associated with severe hemodynamic impairment (38). Organization of atrial fibrillation into atrialfluttermay occur during pharmacologic therapy and may be associated with a significant heart rate increase. This is usually due to a drug-induced slowing of theflutterrate. When this occurs, the vagolytic effect of quinidine in combination with decreased anterograde concealed conduction permit 1:1 conduction of theflutterwaves. The exact prevalence of this complication during therapy of atrialfibrillationwith currently used doses of quinidine (800 to 1200 mg of quinidine sulfate daily) is not known. Before the advent of electrical cardioversion, however, when doses of 3200 mg daily were routinely used in attempts to convert atrial fibrillation to sinus rhythm (39), the development of atrialflutterwas common. In a series of 115 patients with atrialfibrillationtreated with this dose of quinidine in conjunction with digitalis (40), atrial flutter developed in 66 patients. Three patients with atrial flutter had 1:1 AV conduction, which represents 2.6% of all patients treated (4.5% of those developing flutter). Conversion of atrial fibrillation to flutter in patients treated with the lower doses of quinidine currently in use appears to be relatively infrequent and 1:1 conduction is very rarely seen. At most, any increase in ventricular response to atrial fibrillation provoked by quinidine is modest and is rarely clinically significant. Nevertheless, physicians frequently prescribe digoxin concomitantly with quinidine before attempting cardioversion and continue it as maintenance therapy after reversion to sinus rhythm. In a patient who has had poor rate control during atrialfibrillationwhile receiving digoxin or who has a tendency to develop atrial flutter alternating withfibrillation,serious consideration should be given to combining quinidine with a small dose of a beta-blocking agent rather than with digoxin, because the latter agent may be ineffective under conditions of heightened sympathetic tone (41, 42). Controversy exists regarding the need for concomi-

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tant digoxin use when quinidine is used to maintain sinus rhythm. In a comparative study of quinidine sulfate and sotalol for the maintenance of sinus rhythm after cardioversion (28), quinidine-treated patients reverting to atrial fibrillation had a statistically higher ventricular rate than at baseline (that is, before cardioversion), but the presence or absence of concomitant digoxin therapy did not affect the mean ventricular rate. No details of digoxin dose or serum levels were given, and therefore inadequate dosage of digoxin as a factor contributing to the increased rate, although unlikely, cannot be excluded. Other 14 Agents Both disopyramide (43) and procainamide have been associated with an accelerated ventricular response during atrial flutter and therefore may cause a paradoxical heart rate increase if atrial fibrillation converts to flutter during therapy. The negative inotropic effect of disopyramide (44) in conjunction with a rapid ventricular response may be particularly harmful. Lidocaine Lidocaine therapy is generally considered of value only for ventricular arrhythmias but may occasionally be prescribed when ventricular arrhythmias and atrial fibrillation coexist. A mild and inconsistent increase in AV conduction produced by lidocaine has been shown (45), but the effects of lidocaine on the atrium are not well recognized. Isolated case reports have documented an increase in the ventricular response during lidocaine therapy given for ventricular arrhythmias to patients who also have atrial flutter (46, 47). Danahy and Aronow (48), in a systematic study of this phenomenon, reported on 18 patients with atrial flutter and 35 patients with atrial fibrillation given 100 mg of intravenous lidocaine. A decrease in atrial rate, with a nadir at 1 to 2 minutes, occurred in all patients with atrialflutter,three of whom increased their ventricular response by more than 20 beats per minute. Of the patients with atrial fibrillation, three (8.6%) had a heart rate increase of more than 20 beats/min with a maximum increase of 40 to 50 beats/ min. The concomitant use of quinidine appeared to be associated with a greater lidocaine-induced increase in ventricular response. In consideration of these observations, it appears prudent to be cautious about using lidocaine to treat ventricular arrhythmias in patients with atrial fibrillation, particularly if quinidine therapy has been started. Type IC Antiarrhythmic Agents Clinical trials of IC agents have shown efficacy of these agents for terminating recent-onset atrial fibrillation or for maintaining sinus rhythm after cardioversion (29-31, 49, 50). These drugs are generally well tolerated. The use-dependent effect of these agents results in increasing degrees of fast-channel blockade as stimulation rates are increased (35). This phenomenon, although not unique to type IC agents, is most prominent with this class of drugs and can result in a marked QRS widening at rapid ventricular rates.

As with other antiarrhythmic drugs, flecainide, encainide, and propafenone may organize and slow the rate of atrial fibrillation and convert it to atrial flutter with a slow enough atrial rate for 1:1 conduction to occur. When this happens, the rapid ventricular response is often aberrantly conducted with bizarre, wide complexes resulting in an electrocardiogram that may be confused with ventricular tachycardia (51). Murdock and colleagues (52) noted the occurrence of atrial flutter in 14 of 82 patients treated with propafenone for atrial fibrillation, three of whom developed 1:1 AV conduction with ventricular rates of 200 to 275 beats per minute and QRS widths of up to 160 ms. A similar phenomenon has been observed during therapy with flecainide and encainide (53) and has been described in 3.5% of patients receiving the investigational IC agent, recainam (54). The overall incidence of the transformation of atrial fibrillation toflutterwith IC agents appears to be in the range of 3.5% to 5%. Because significant hemodynamic compromise may occur if the onset of flutter is associated with an increased ventricular response, it has been suggested that concomitant beta-blocking agents, digoxin, or calcium-channel blockers should be also prescribed when using IC agents to treat atrial fibrillation, particularly if atrial flutter has previously occurred (51, 52). The safety of verapamil combined with flecainide has been shown in a small, selected series of patients (31), but caution is warranted in patients with reduced ventricular function in view of the potential for substantial additive negative inotropic effects. Further studies are needed before the value of this combination can be accurately assessed. Digoxin, in combination with flecainide, has a modest effect in controlling the ventricular rate during exercise in patients with atrial fibrillation (55), but there is no firm evidence that its use will be adequate to prevent 1:1 conduction should atrial flutter occur. As with verapamil, beta-blocking agents are potentially negatively inotropic when used in conjunction with IC agents (56), although this combination is probably safe in the presence of normal ventricular function. In selected patients, beta-blockers have been shown to be effective in preventing the ventricular proarrhythmic effects of flecainide and to be well tolerated despite a reduced ejection fraction (57). Aggravation of Paroxysmal Atrial Fibrillation In patients with chronic atrial fibrillation, true aggravation of the arrhythmia is not feasible. Conversely, isolated atrial premature beats so rarely need therapy that no data exist on the likelihood of converting isolated beats to sustained atrial tachycardia, flutter, or fibrillation. Even the examples of conversion of fibrillation to flutter with increased ventricular response, described above, are not true examples of proarrhythmia but rather reflect an incomplete manifestation of the desired properties of the drug—namely an organization of atrial activity. Paroxysmal atrial fibrillation offers a possibility to examine the incidence of aggravation of arrhythmia in terms of increased frequency and duration of episodes,

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although the sporadic nature of this arrhythmia defies attempts to formalize criteria for an exact definition of atrial proarrhythmia (58, 59). Coumel (60) has described a group of patients in whom increased parasympathetic tone may precipitate paroxysms of atrial fibrillation. These patients almost always have a structurally normal heart, and drugs that increase vagal tone (such as digoxin) or that cause sinus bradycardia (such as betablockers) may increase the frequency or duration of the paroxysms. The frequency with which digoxin use prolongs episodes of paroxysmal atrial fibrillation is not known but it may be more common than realized. In a group of patients with recent-onset atrial fibrillation without heart failure who were treated with either digoxin or placebo, we (61) found no benefit of digoxin in terminating the arrhythmia, but there was a tendency for those in the digoxin group who later reverted to sinus rhythm to remain in atrial fibrillation longer than did those in the placebo group. A similar observation was made by Rawles and associates (62) who found that patients treated with digoxin who had paroxysmal atrial fibrillation had significantly more episodes lasting 30 minutes or longer than did patients not on digoxin (relative risk, 4.3). The tendency of digoxin to prolong episodes of atrial fibrillation in certain patients may occasionally transform paroxysmal to sustained atrial fibrillation; this has been used therapeutically to reduce symptoms associated with the paroxysmal onset of the arrhythmia (63). In a patient with troublesome, drug-resistant atrial fibrillation who is receiving maintenance digoxin, it is my practice to stop digoxin and reassess the arrhythmia, occasionally with gratifying results. Verapamil and Diltiazem Calcium-channel blockers are commonly used to control heart rate in atrial fibrillation. These drugs have been incriminated in prolonging, and occasionally precipitating, atrial fibrillation, although the exact mechanism remains unclear. In animals, verapamil has been shown to increase the inducibility and persistence of atrial fibrillation (64). We have described the development of atrial fibrillation in a normal person after a 10-mg injection of verapamil (65). Sustained atrial fibrillation has also been described after AV nodal tachycardia was terminated with this drug (66). Shenasa and coworkers (67) have systematically examined the hypothesis that calcium-channel blockers precipitate or increase the duration of an episode of atrial fibrillation. They studied 18 patients undergoing an electrophysiology study who had documented paroxysmal atrial fibrillation and who were in sinus rhythm at the time of the study. The arrhythmia was induced at baseline in 17 of the 18 patients and lasted for a mean of 31 ± 12 minutes. After intravenous verapamil or diltiazem was administered, atrial fibrillation persisted for 112 ± 49 minutes. In patients given oral verapamil, the induced arrhythmia lasted 69 ± 35 minutes. A similar phenomenon was noted in 17 patients who had never had spontaneous arrhythmia, although the ease of induction and the duration of sustained arrhythmia were 146

less than in those with spontaneous paroxysmal fibrillation. Calcium-channel blockers have little demonstrable effect on the intact human atrium (68, 69), and it has been suggested that changes in sympathetic tone due to acute vasodilation may provoke or sustain atrial fibrillation. The finding that the oral forms of diltiazem and verapamil cause induced atrial fibrillation to persist, however, suggests that the mechanism cannot be fully explained on the basis of autonomic changes (70). Although the mechanism is unclear, the available evidence suggests that these agents do have a tendency to prolong episodes of atrial fibrillation and perhaps occasionally to produce it in susceptible subjects. The prevalence of this phenomenon is not known. Adverse Effects of Drugs in Atrial Fibrillation Associated with the Wolff-Parkinson-White Syndrome Calcium-Channel Blockers In patients with the WPW syndrome and a short refractory period of the accessory pathway, the ventricular response to atrial fibrillation may be exceedingly rapid, and spontaneous ventricular fibrillation may sometimes ensue (71). Several reports have documented the adverse effects of verapamil in preexcited atrial fibrillation (71-73). McGovern and colleagues (73) reported on five patients with the WPW syndrome and atrial fibrillation who had had ventricularfibrillationor profound hypotension after 5 to 10 mg of intravenous verapamil was administered. Review of tracings available before and after verapamil administration revealed the sudden development of ventricular fibrillation in three patients and a marked increase in ventricular response in two, suggesting a cause-and-effect relationship. Subsequent electrophysiologic testing in a drug-free state documented a very short refractory period of the bypass tract in all patients, characterized by a short R-R interval (160 to 200 ms) in induced atrial fibrillation. The mechanism of clinical deterioration after administration of intravenous verapamil to a patient with the WPW syndrome who has atrial fibrillation is unclear but is probably multifactorial. Acceleration of the ventricular response may occur as a result of increased AV nodal blockade, which secondarily causes decreased retrograde concealed conduction in the accessory pathway (74). Alternatively, the rate increase may be secondary to increased sympathetic tone provoked by drug-induced vasodilation. The negative inotropic effect of verapamil may also contribute to hemodynamic deterioration in patients who are barely compensating for the extremely rapid rate. A further decrease in stroke volume, already reduced by ventricular dyssynergy caused by preexcited beats, may be of importance. Whatever the mechanism, it is clear that verapamil has no role in the management of atrial fibrillation in patients with the WPW syndrome. Unfortunately, a study by Garratt and colleagues (75) indicates that the diagnosis of preexcited atrial fibrillation is often not considered, and verapamil still continues to be given in error with serious consequences. The Wolff-Parkinson-White syndrome most com-

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monly manifests itself as an atrioventricular reciprocating tachycardia. Anterograde conduction almost invariably occurs down the AV node resulting in a narrowcomplex, regular tachycardia. Although subtle clues to the cause of the tachycardia may be present on the surface ECG (76), it is generally difficult to distinguish this arrhythmia from that caused by re-entry limited to the AV node unless a previous ECG during sinus rhythm that shows ventricular pre-excitation is available. Adenosine is rapidly gaining favor as the initial treatment for narrow-complex reciprocating tachycardias and it has not been reported to provoke sustained atrial fibrillation (77, 78). Although adenosine is an excellent first-choice agent for AV tachycardia or AV nodal tachycardia, it is much more costly than verapamil and there are some patients in whom verapamil might be a more effective or better tolerated drug. These include persons with asthma, those receiving aminophylline, and patients with an early recurrence of the tachycardia after conversion (78). For regular narrow-complex tachycardias, verapamil is still commonly a drug of first choice (79). The uncommon but important tendency of calcium-channel blockers to convert re-entrant tachycardia into atrial fibrillation (66), however, may be hazardous in patients with a bypass tract and has been reported to cause preexcited atrial fibrillation with a rapid ventricular response and consequent hemodynamic compromise (80). Such an occurrence, although probably quite rare, suggests the need for the availability of electrical cardioversion should clinical deterioration occur. The very rare provocation by verapamil of preexcited atrial fibrillation in susceptible patients should not be a reason to avoid using this drug for narrow-complex re-entrant tachycardia. Digoxin Digoxin, a traditional agent for rate control in atrial fibrillation, has minimal effects on an accessory pathway and acceleration of ventricular response resulting in ventricular fibrillation, may occur (72, 81). Consequently, digoxin should not be administered for atrial fibrillation with a preexcited ventricular response. Beta-Blockers Although beta-blocking agents also have no significant effects on accessory pathway conduction (82) and are thus not indicated in atrial fibrillation associated with the WPW syndrome, reports of significant adverse effects are rare. Nevertheless, acceleration of the ventricular response has been reported and may be considerable (83). Lidocaine Lidocaine presents an interesting therapeutic problem in patients with preexcited atrial fibrillation, because this arrhythmia is often misdiagnosed as ventricular tachycardia—an arrhythmia for which lidocaine may be highly effective. Early reports suggested that lidocaine was effective in slowing conduction through an accessory pathway (82) and in controlling the ventricular response to pre-excited atrial fibrillation (84). Subsequent studies, however, have found no consistent ef-

fects on accessory pathway conduction, and Akhtar (85) actually noted a decrease in the RR interval during induced atrial fibrillation in five of eight patients with the WPW syndrome receiving lidocaine, two of whom had clinically significant hemodynamic deterioration. The exact incidence of serious hemodynamic effects of lidocaine given for the WPW syndrome in clinical practice is not known, but the absence of published reports suggests that it is rare, and this agent is still considered of value by some authorities. Amiodarone An unusual case of ventricular rate acceleration has been reported after intravenous amiodarone therapy for preexcited atrial fibrillation in a patient with a previous inferior wall infarction (86). Amiodarone has been widely and successfully used for patients with the WPW syndrome, and such an occurrence appears distinctly unusual. Digoxin Cardiotoxicity Cardiac arrhythmias are a well-known manifestation of digoxin toxicity (87, 88), although the prevalence of toxicity appears to have decreased considerably during the last 20 years because of an increased awareness of the factors predisposing to toxicity and the availability of accurate serum digoxin measurements. In a study done in 1969 (89), 31 of 135 (23%) patients who were receiving digoxin when hospitalized were considered definitely digoxin toxic. In contrast, in 1987, only 5 of 563 (0.8%) patients receiving digoxin at hospital admission met criteria for digoxin toxicity (90). Despite the marked reduction in the prevalence of digoxin toxicity, it remains a challenging problem in patients with atrial fibrillation in whom the emergence of junctional rhythm, manifested as the regularization of cardiac rhythm, may represent the first indication of digoxin overdose (91). Progression to junctional rhythm with Wenckebach block leads to a regularly irregular rhythm which, to the untrained eye, may be mistaken for the irregularly irregular ventricular response of atrial fibrillation. As in sinus rhythm, ventricular bigeminy and ventricular tachycardia may occur, progressing, in rare instances, to a classical ventricular bidirectional tachycardia. Recognition of digoxin toxicity is particularly important in patients undergoing cardioversion, because the electric shock may expose serious ventricular arrhythmias. The diagnosis of digoxin toxicity may be particularly difficult in patients with atrial fibrillation receiving verapamil or diltiazem because these agents may cause regularization of the ventricular response unrelated to digoxin (92) or verapamil may elevate serum digoxin levels, thereby precipitating digoxin toxicity (93). Although serum digoxin levels correlate poorly with digoxin toxicity, particularly in atrial fibrillation, a high digoxin level in conjunction with a suspicious rhythm is suggestive of toxicity and should mandate a trial of dose reduction. Careful attention to serum levels of potassium and magnesium, with maintenance well within the normal range, is necessary to reduce the risk for digoxin-induced arrhvthmia.

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Drug-induced Bradycardia Because atrial fibrillation is generally associated with a rapid ventricular response, the aim of therapy is often to normalize the ventricular rate. Digoxin, beta-blockers, or calcium-channel blocking agents may sometimes be required to treat symptomatic exertional tachycardia in a patient whose resting ventricular response is normal (42). Occasionally, this may result in excessive rate slowing at rest requiring permanent pacing to safely administer drug therapy (94). Atrial fibrillation is commonly a concomitant manifestation of sinus node disease and under these circumstances paroxysmal atrial fibrillation may be followed by symptomatic periods of sinus arrest. Although pharmacologic control of tachycardia may prevent the post-tachycardia pauses (95), incomplete tachycardia control may cause worsening of post-tachycardia bradycardia as a result of further, drug-induced sinus node depression. Virtually all antiarrhythmic agents including digoxin, beta-blockers, and calcium-channel blockers have been implicated in the aggravation of the sick sinus syndrome (96-102). Thus the aggravation or precipitation of posttachycardia pauses should be considered in the differential diagnosis of patients treated for paroxysmal atrial fibrillation who develop dizziness or syncope, particularly if excessive pauses have previously been noted. Because atrial fibrillation may be one manifestation of widespread disease of the conduction system, atrial antiarrhythmic agents may occasionally also precipitate AV block arising within or, less commonly, below the AV node. Aberrant Ventricular Conduction Although it is not a true proarrhythmic effect, it is important to recognize the phenomenon of aberrant ventricular conduction (103) precipitated by antiarrhythmic agents. It is more frequently seen with type IC agents (flecainide and propafenone). These agents have a strong use-dependent effect, which results in their effects on conduction becoming more prominent at faster stimulation rates (35). Recurrence of an atrial arrhythmia conducted with drug-induced aberrant ventricular conduction may result in misinterpretation of the ECG as ventricular tachycardia, causing inappropriate discontinuation of therapy. Newly defined criteria for distinguishing ventricular tachycardia from aberrant conduction may be helpful in determining the origin of a wide-complex tachycardia (104), but these criteria may not be as sensitive and specific in drug-induced aberration compared with aberrant conduction in the drug-free state (80, 104, 105). Some clues to aberrant conduction may exist. Atrial fibrillation with a rapid ventricular rate and associated aberrant conduction may be suspected by the findings of an irregular ventricular rhythm (51) and adenosine injection may be helpful in transiently exposing P waves in atrial flutter with 1:1 aberrant ventricular conduction (80). Conclusion Pharmacologic treatment of atrial fibrillation can be associated with various disturbances of cardiac rhythm ranging from relatively benign to life-threatening ar148

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rhythmias. Although the prevalence of cardiotoxicity of most drugs used for the therapy of atrial fibrillation is not known, the risk is almost certainly less than when treatment is prescribed for ventricular arrhythmia because the underlying heart disease is often less severe. Nevertheless, the clinician should be attuned to the potentially adverse effects of these agents and, as with any therapy, atrial antiarrhythmic drugs should only be instituted after careful consideration of the risks and benefits in an individual patient. It is also important to recognize that side effects may occasionally appear after therapy has been well tolerated for weeks or months. When this occurs a careful search should be undertaken for precipitating factors such as medication changes, electrolyte shifts, or deterioration in ventricular function. If these guidelines are followed, I believe that despite their potential for causing serious problems, anti-arrhythmic drugs are a safe and useful therapy for almost all patients with troublesome atrial arrhythmias. Requests for Reprints: Rodney H. Falk, MD, Boston City Hospital, Division of Cardiology, Talbot 227W, 818 Harrison Avenue, Boston, MA 02118. Current Author Address: Dr. Falk: Boston City Hospital, Division of Cardiology, Talbot 227W, 818 Harrison Avenue, Boston, MA 02118. References 1. Velebit V, Podrid P, Lown B, Cohen BH, Graboys TB. Aggravation and provocation of ventricular arrhythmias by antiarrhythmic drugs. Circulation. 1982;65:886-94. 2. Morganroth J, Anderson JL, Gentzkow GD. Classification by type of ventricular arrhythmia predicts frequency of adverse cardiac events from flecainide. J Am Coll Cardiol. 1986;8:607-15. 3. Horowitz LN, Zipes DP, Bigger JT Jr, Campbell RW, Morganroth J, Podrid PJ, et al. Proarrhythmia: arrhythmogenesis of aggravation or arrhythmia—a status report, 1987. Am J Cardiol. 1987;59: 54E-56E. 4. Minardo JD, Heger JJ, Miles WM, Zipes DP, Prystowsky EN. Clinical characteristics of patients with ventricular fibrillation during antiarrhythmic drug therapy. N Engl J Med. 1988;319:257-62. 5. Stanton MS, Prystowsky EN, Fineberg NS, Miles WM, Zipes DP, Heger JJ. Arrhythmogenic effects of antiarrhythmic drug: a study of 506 patients treated for ventricular tachycardia or fibrillation. J Am Coll Cardiol. 1989;14:209-15. 6. Kerr WG, Bender WL. Paroxysmal ventricular fibrillation with cardiac recovery in a case of auricular fibrillation and complete heart block while under quinidine sulfate therapy. Heart. 1922;9:269-78. 7. Binder MJ, Rosene L. Paroxysmal ventricular tachycardia and fibrillation due to quinidine. Am J Med. 1952;12:491-7. 8. Selzer A, Wray W. Quinidine syncope. Paroxysmal ventricular fibrillation occurring during treatment of chronic atrial arrhythmias. Circulation. 1964;30:17-26. 9. Nguyen PT, Scheinman MM, Seger J. Polymorphous ventricular tachycardia: clinical characterization, therapy, and the QT interval. Circulation. 1986;74:340-9. 10. Lown B, Amarasingham R, Neuman J. New method for terminating cardiac arrhythmias—use of synchronized capacitor discharge. JAMA. 1962;182:548-55. 11. Lown B. Electrical reversion of cardiac arrhythmias. Br Heart J. 1967;29:469-89. 12. Radford MD, Evans DW. Long-term results of DC reversion of atrial fibrillation. Br Heart J. 1968;30:91-6. 13. Oram S. The dysrhythmias. In: Oram S. Clinical Heart Disease. 2d ed. London: Heinemann Medical Books; 1981:638-42. 14. Coplen SE, Antman EM, Berlin JA, Hewitt P, Chalmers TC. Efficacy and safety of quinidine therapy for maintenance of sinus rhythm after cardioversion. Circulation. 1990;82:1106-16. 15. Roden DM, Woosley RL, Primra RK. Incidence and clinical features of the quinidine-associated long QT syndrome: implications for patient care. Am Heart J. 1986;111:1088-93. 16. Roden DM, Hoffman BF. Action potential prolongation and induction of abnormal automaticity by low quinidine concentrations in canine Purkinje fibers. Relationship to potassium and cycle length. Circ Res. 1985;56:857-67. 17. Jackman WM, Friday KJ, Anderson JL, Allot EM, Clark M, Lazzara R. The long QT syndromes: a critical review, new clinical

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46. Adamson AR, Spracklen FH. Atrial flutter with block—contraindication to the use of lignocaine. Br Med J. 1968;2:223-4. 47. Marriott HJ, Bieza CF. Alarming ventricular acceleration after lidocaine administration. Chest. 1972;61:682-3. 48. Danahy DT, Aronow WS. Lidocaine-induced cardiac rate changes in atrial fibrillation and atrial flutter. Am Heart J. 1978;95:474-82. 49. Bianconi L, Boccadamo R, Pappalardo A, Gentili C, Pistolese M. Effectiveness of intravenous propafenone for conversion of atrial fibrillation and flutter of recent onset. Am J Cardiol. 1989;64:335-8. 50. Porterfidd JG, PorterfieW LM. Therapeutic efficacy and safety of oral propafenone for atrial fibrillation. Am J Cardiol. 1989;63:114-6. 51. Cryns HJ, van Gelder IC, Lie KI. Supraventricular tachycardia mimicking ventricular tachycardia during flecainide treatment. Am J Cardiol. 1988;62:1303-6. 52. Murdock CJ, Kyles AE, Yeung-Lai-Wah JA, Qi A, Vorderbrugge S, Kerr CR. 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In spite of illness, in spite even of the archenemy sorrow, one can remain alive long past the usual date of disintegration if one is unafraid of change, insatiable in intellectual curiosity, interested in big things, and happy in small ways. Edith Wharton A Backward Glance Edith Wharton: Novellas and Other Writings The Library of America, 1990, p. 767

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