Proarrhythmia

CARDIAC ARRHYTHMIAS

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PROARRHYTHMIA Gerald V. Naccarelli, MD, Deborah L. Wolbrette, MD, and Jerry C. Luck, MD

Although antiarrhythmic drugs are used frequently in the suppression of symptomatic and life-threatening arrhythmias, adverse effects, such as subjective and end-organ toxicity, negative inotropy, and proarrhythmia, are associated with such treatment. The term proarrhythmia is broadly defined as the aggravation of an existing arrhythmia or the development of a new arrhythmia during antiarrhythmic drug therapy. Although proarrhythmia may be a manifestation of toxic levels of antiarrhythmic drugs, its occurrence may be idiosyncratic and occur early after therapy is instituted. This article defines the various types of proarrhythmia, compares the proarrhythmia potential of various antiarrhythmic drugs, defines high-risk patient subgroups, and details strategies to avoid and treat proarrhythmia. DEFINITION OF PROARRHYTHMIA

Criteria for the spontaneous occurrence of proarrhythmia have been proposed (see the accompanying box l)." Using noninvasive methods, Velebit et a161proposed that a proarrhythmia exists if there is (1) a 4-fold increase in the frequency of premature ventricular contractions (PVCs) compared with control; (2) a 10-fold increase of repetitive form, such as couplets or runs of ventricular tachycardia (VT); or (3) the occurrence of sustained VT not present during control monitoring. The use of these criteria is limited in patients with low-density From the Department of Medicine (GVN, DLW, JCL), Division of Cardiology (GVN), Cardiac Pacing and Electrocardiography (DLW), and Clinical Electrophysiology UCL), Cardiovascular Center, Pennsylvania State University College of Medicine, The Milton Hershey Medical Center, Hershey, Pennsylvania MEDICAL CLINICS OF NORTH AMERICA VOLUME 85 NUMBER 2 MARCH 2001

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arrhythmias at baseline because spontaneous variability may be the more likely explanation in many patients who fit these criteria. To compensate for baseline arrhythmia frequency, Morganroth and Horowitz3*proposed alternate Holter monitor criteria (see the first box) for aggravation based on baseline PVC frequency. Random variability of arrhythmia occurrence can mimic antiarrhythmic drug effect and aggravation. Spontaneous variability poses a significant problem in defining arrhythmia aggravation based on increase in PVC, couplets, and nonsustained VT frequency. In the Cardiac Arrhythmia Pilot Study (CAPS),ll proarrhythmia criteria were met in 3% of patients treated with placebo because of the confounding effects of this type of arrhythmia variability. Longer periods between recording times may make variability more marked. Recognition of drug-induced proarrhythmic effects in a patient with a preexisting arrhythmia can be difficult because spontaneous recurrence of arrhythmia resulting from random variability may mimic proarrhythmia. In general, mild, minimally symptomatic increases in spontaneous ventricular ectopy, couplets, and nonsustained runs of VT are not life-threatening. Whether this increase represents early proarrhythmia, spontaneous variability, or drug inefficacy often is difficult to determine. In practice, the authors do not consider the above-mentioned a proarrhythmic response. More specific criteria of spontaneously occurring ventricular proarrhythmia emphasize the life-threatening forms of ventricular proarrhythmia and include the development of a new arrhythmia, such as torsades de pointes; the conversion of nonsustained VT to sustained VT; and the development of new non-pause-dependent polymorphic VT, ventricular fibrillation (VF), or incessant VT. Electrophysiology testing may be useful in recognizing proarrhythmia that may not be noted using electrocardiogram (ECG) monitoring techniques. Criteria for proarrhythmia during electrophysiology testing have been proposed by Horowitz et all9 (see the second box). The best invasive criterion of proarrhythmia is the induction of incessant VT. Other criteria are flawed by the variability of VT induction and the possible induction of a nonclinical arrhythmia. Ruskin et a152could not induce VT or VF in any of six antiarrhythmic drug-free patients who had survived a cardiac arrest while taking an antiarrhythmic drug. After restarting the offending antiarrhythmic, however, VT or VF was induced in four of the six patients during repeat programmed ventricular stimulation.

Proposed Definitions of Proarrhythmia Comparing the Results of Noninvasive Monitoring Before and After Antiarrhythmic ' Drug Therapy 1. New onset of arrhythmia not present before drug therapy a. Bradyarrhythmias, involving sinus node, atrioventricular node, and His-Purkinje system b. Supraventricular extrasystoles and tachyarrhythmias c. Premature ventricular contractions d. Nonsustained ventricular tachycardia

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3. 4. 5.

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e. Sustained monomorphic ventricular tachycardia f. Sustained polymorphic ventricular tachycardia g. Torsades de pointes h. Ventricular fibrillation Increased frequency of arrhythmia on 24-hour Holter monitoP a. Mean number of premature ventricular Increase to define proarrhythmia contractionslh off drug 1-50 x 10 51-100 x 5 101-300 x 4 > 300 x 3 b. Nonsustained ventricular tachycardia: 10 x increase in mean hourly frequency of ventricular tachycardia complexes Spontaneous sustained ventricular tachycardia or ventricular fibrillation that is significantly more difficult to terminate or that cannot be terminated Incessant ventricular tachycardia Sudden death soon after initiating antiarrhythmic treatment or increasing dose

Data from Kutalek SP, McCormick DJ, Porter RS: The concept of proarrhythmia. In Naccarelli GV (ed): Clinical Cardiovascular Therapeutics: Cardiac Arrhythmias: A Practical Approach. Mt Kisco, NY, Futura, 1991; pp 397-412.

Proposed Definitions of Proarrhythmia Comparing the Results of Cardiac ElectrophysiologyTesting Before and After Antiarrhythmic Drug Therapy

New induction of ventricular tachycardia Conversion of induced nonsustained ventricular tachycardia to sustained ventricular tachycardia or ventricular fibrillation Conversion of stable monomorphic ventricular tachycardia to polymorphic ventricular tachycardia or ventricular fibrillation Increase in the rate of induced ventricular tachycardia New requirement for electric cardioversion to terminate sustained ventricular tachycardia Induction of incessant ventricular tachycardia Induction of arrhythmia with less aggressive stimulation protocol (i.e., fewer extrastimuli or at a slower paced cycle length) Death from induced sustained ventricular tachycardia or ventricular fibrillation Data from Horowitz LN, Greenspan AM, Rae AP, et al: Proarrhythmic response during electrophysiologic testing. Am J Cardiol 59:45E-48E, 1987.

TIMING OF PROARRHYTHMIA

Most proarrhythmias occur early after the initiation of antiarrhythmic drugs. Many investigators have suggested that this close association

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is a criterion for the occurrence of proarrhythmia. Late-occurring proarrhythmias may occur, however, although the true incidence of late proarrhythmia with various agents has not been e~tab1ished.l~.41 Many of these episodes may have been misclassified as tolerance, ineflcacy, or secondary to other medication changes made over time. The timing of proarrhythmic responses has clinical implications for the in-hospital initiation of antiarrhythmic drugs under telemetry conditions. Because 30% to 50% of proarrhythmic responses occur greater than 4 days after initiating therapy, in-hospital initiation of antiarrhythmic drugs does not capture all proarrhythmic events.

SPECIFIC TYPES OF LIFE-THREATENING PROARRHYTHMIA New-Onset, Sustained, Monomorphic Ventricular Tachycardia

The first occurrence of spontaneous monomorphic, sustained VT soon after initiating antiarrhythmic therapy in a patient without previous sustained VT is considered a proarrhythmic response in all proarrhythmia criteria schemas. This type of proarrhythmia is most likely to occur in a patient treated for nonsustained VT in the presence of organic heart disease and left ventricular dysf~nction.~ The induction of sustained VT by programmed stimulation in a post-myocardial infarction patient with nonsustained VT and a depressed ejection fraction can be achieved about 30% of the time. This occurrence probably identifies a patient at high risk for the spontaneous occurrence of sustained VT or VF and not a proarrhythmic response. The Multicenter Unsustained Tachycardia Trial (MUST") and the Multicenter Automatic Implantable Defibrillator Trial (MADIT) reported that about 30% of post-myocardial infarction patients with nonsustained VT have inducible sustained VT by programmed 35 electric stim~lation.~,

Increased Frequency of Sustained Ventricular Tachycardia

The occurrence of an increased frequency of sustained VT in a patient with a clinical history of ventricular tachyarrhythmias often is classified as a proarrhythmic response. This condition often may be secondary to a spontaneous recurrence and inefficacy of the antiarrhythmic drug, however. Increasing the drug dose further in this situation may lead to worsening of the arrhythmia (slower, more frequent sustained VT) or may cure the arrhythmia if it represented inefficacy secondary to inadequate antiarrhythmic blood levels.

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Incessant Ventricular Tachycardia

Incessant VT can occur during antiarrhythmic therapy. In all proarrhythmia definition schemas, this form of proarrhythmia is considered a definite proarrhythmic response. The class 1C agents have been associ17, 31, 48, ated with the highest occurrence of this type of pr~arrhythmia.~, 56, 58, These drugs slow conduction profoundly with minimal effects of refractoriness; these drugs may alter the balance between refractoriness and conduction in an arrhythmogenic zone. The occurrence of this tachycardia is most common in patients with a history of sustained VT associated with left ventricular dysfun~tion.~~, 55 These arrhythmias are more likely to occur with higher doses or inappropriate rapid dose escalations with these agents. The incessant VT is characterized by a wide-complex, sine wavelooking tachycardia that has broad, undulating complexes (Fig. 1A). The rate of the tachycardia is usually slower than that of a spontaneous tachycardia. These drug-induced tachycardias often cannot be terminated by pacing or cardioversion (Fig. 1B). Incessant VT may be sustained in nature or have long runs of nonsustained VT with periodic sinus beats and quick resumption of paroxysms of VT. Although typical of class 1C agents, incessant VT also has been noted with other antiarrhythmic agents. Torsade de Pointes

Torsade de pointes is a specific type of proarrhythmia that occurs secondary to certain antiarrhythmic and other Q-T-prolonging agents. Dessertenne13described torsades de pointes as twisting around the points. It has been described classically as a pause-dependent, polymorphic VT associated with Q-T interval prolongation (Figs. 2 and 3). Selzer and reported in 1964 that many cases of quinidine syncope were secondary to polymorphic VT. The mechanism of this arrhythmia is controversial, although it appears to be secondary to enhanced early after-depolarizations.20Because prolongation of the Q-T interval seems to be crucial for the formation of this arrhythmia, the class IA antiarrhythmic drugs, quinidine, procainamide, and disopyramide, and the class I11 antiarrhythmic agents, sotalol and dofetilide, that block the delayed rectifier potassium current have the highest frequency of causing this arrhythmia.4, 25, 50, 54 These drugs have caused torsades de pointes in 5% of cases.*,54 The previously mentioned class IA and I11 agents show reverse use-dependent effects with more profound changes in action potential duration at new rates than normal test rates. A similar risk of torsades de pointes has been associated with the use of the class I11 intravenous antiarrhythmic, ibutilide." Amiodarone, which is a class I11 agent that also prolongs the Q-T interval, is rarely associated with this form of proarrhythmia.8The low incidence of amiodarone-induced torsades de pointes may be related

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Figure 1. A, A 12-lead electrocardiogram demonstrating incessant VT with a sine wave morphology in a patient treated with encainide. B, Rhythm strip of patient in Figure IA demonstrating incessant VT. Cardioversion (DC) did not revert the VT to sinus rhythm confirming incessant nature of VT.

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Figure 2. Development of short runs of pause-dependent torsade de pointes in a patient treated with quinidine for atrial fibrillation. Note giant U waves (arrows).

Figure 3. Rhythm strip demonstrating pause-dependent polymorphic torsade de pointes in a patient treated with quinidine for atrial fibrillation.

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to its lack of reverse-use dependence and less effect on prolonging action potential duration in the M cell region than other class IA and I11 agents. Most amiodarone-induced episode of torsades de pointes occur when the drug is used in combination with a type IA antiarrhythmic agent. Class IB antiarrhythmics and p-blocking agents, which shorten the Q-T interval, may be a treatment for this syndrome. Class IC agents have little effect on repolarization and are only rarely associated with this malignant form of proarrhythmia. Although torsade de pointes may be secondary to an antiarrhythmic drug overdose with marked prolongation of the Q-T interval, some episodes are idiosyncratic and may occur after only a few doses of antiarrhythmic drugzn Jackman et alZnnoted, however, that 18 of 38 episodes of torsade de pointes in their series occurred 6 or more days after the initiation of therapy. Roden et a150 noted that 4 of 24 patients develop torsade de pointes greater than 1 year after initiating therapy. Classically, torsade de pointes has a polymorphic, pause-dependent VT morphology with the presence of U waves. Pause-dependent, monomorphic VT in the presence of giant U waves also may be caused by a similar electrophysiologic mechanism, however.z0 A close relationship between Q-T prolongation and the development of torsade de pointes has not been well establishedznfor class IA agents. In an attempt to avoid torsades de pointes with class IA drugs, clinicians usually avoid marked prolongations of Q-T intervals greater than 600 ms. Although this Q-T cutoff is used routinely, there are few scientific data available to confirm this suggested approach. With sotalol and dofetilide, Q-T prolongation and higher doses increase the risk of torsades de pointes. For sotalol, avoiding Q-T, greater than 525 ms and doses greater than 320 mg decreases the incidence of torsades de pointes from 5% to less than 2%. In general, it is recommended that patients who have baseline prolongation of the Q-T interval should not be given drugs that prolong action potential duration. The use of combination antiarrhythmic therapy of a class IA and IB agent may minimize QT prolongation; however, well-controlled studies need to verify this hypothesis. Many other factors are related to the development of Q-T prolongation, including concomitant therapy with other drugs that prolong action potential duration (e.g., phenothiazines), the presence of congenital prolonged Q-T syndrome, hypokalemia, hypocalcemia, hypomagnesemia, diuretic use, female gender, renal dysfunction, and severe bradycardia. Drugs that inhibit the P450A4 system can decrease the metabolism of drugs such as quinidine and should not be used concomitantly. DRUG-INDUCED CARDIAC ARREST

Minardo et alZ9analyzed 30 episodes of drug-induced VF in 20 patients. Fifteen episodes occurred during quinidine therapy; 11, during procainamide therapy; and 6, during disopyramide treatment. Class IA

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agent-induced VF occurred after a median of only 3 days of drug treatment, and greater than 70% of episodes occurred within 5 days. The ejection fraction was lower in the study group compared with controls, and concomitant treatment with digitalis and diuretics was more common in the study group. All measured serum drug concentrations were therapeutic. Hypokalemia often was present, and 25 of the 40 patients were receiving digitalis. The baseline Q-Tc was slightly longer (0.47 versus 0.44) in the study group compared with controls. Both groups had similar Q-T prolongation during drug therapy, however. Four of the 13 patients (31%)had a second episode while receiving a different one of these three agents. Many of these patients responded eventually to amiodarone therapy, and 3 responded to mexiletine therapy without the development of further spontaneous VF. Nine patients received no further drug treatment. Six patients died suddenly during the follow-up period of 18 months. Patients who have a suspicious drug-induced cardiac arrest should undergo extensive evaluation, including an electrophysiology study off antiarrhythmic drugs.52In some patients with otherwise less serious ventricular arrhythmias, the proper treatment may be avoidance of antiarrhythmic therapy instead of aggressive antiarrhythmic therapy or an implantable cardioverter defibrillator. DRUG-INDUCED BRADYARRHYTHMIAS

Drug-induced bradyarrhythmias commonly occur.4, Significant drug-induced bradyarrhythmias may occur (often in patients with suspected sinus node dysfunction) by slowing sinus node automaticity with such drugs as P-blockers, amiodarone, sotalol, flecainide, and propafenone. In some cases, drugs may cause sinoatrial exit block. The development of advanced or complete atrioventricular (AV) block at the level of the AV node may occur with such drugs as digitalis, P-blockers, verapamil, diltiazem, amiodarone, or sotalol. Complete AV block also may occur distal to the bundle of His predominantly with drugs of the class IA or IC subclass. Baseline telemetry and Holter monitoring may screen for baseline abnormalities that should make the physician cautious in using such drugs. Electrophysiology studies may screen for latent sick sinus syndrome, borderline AV block, and markedly prolonged HV intervals. Presence of the aforementioned abnormalities alters the choice of antiarrhythmic drugs to drugs safer to use in patients with these known defects. ATRIAL PROARRHYTHMIA

The accompanying box on p. 513 lists some potential criteria for atrial proarrhythmia.6 The development of atrial tachycardia with digitalis is

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such an example. The presence of a more frequent and chronic incessant atrial flutter is an example of an atrial proarrhythmia; this has been noted with all class IA agents, amiodarone, and most commonly with class IC agents. Periodically, atrial flutter with 1:l AV nodal antiarrhythmic drugs through a combination of slowing atrial rates can cause conduction, improving AV nodal conduction (vagolytic effect or incidental sympathetic ~timulation).~~ Adrenergic events, such as stress testing, may unmask 1:l AV conduction. Because of rapid rates and wide QRS morphology, these tachycardias may be misclassified as ventricular in origin (Fig. 4). Reentrant arrhythmias may occur more frequently, although they are slower after antiarrhythmic therapy. A classic example is with sodium channel blockers used to treat patients with orthodromic

Figure 4. EKG during stress testing demonstrating atrial flutter with 1:l AV conduction simulating VT during flecainide therapy. Note atrial rate postexercise (with advanced AV block) similar to ventricular rate during exercise conforming diagnosis.

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supraventricular tachycardia in the Wolff-Parkinson-White syndrome. Typically, antiarrhythmic drugs slow conduction and prolong refractoriness more in the antegrade than the retrograde direction of the pathway. A premature atrial contraction is more likely to develop unidirectional block and initiate supraventricular tachycardia, although at a slower rate. Similar episodes of more common but slower supraventricular tachycardia can be noted with digitalis, verapamil, or p-blockers.

Criteria for Atrial Proarrhythmia Digitalis-induced atrial tachycardia with atrioventricular block Conversion of paroxysmal atrial fibrillation to chronic, incessant atrial flutter Atrial flutter with new-onset 1:I atrioventricular conduction More frequent, but slower rate, occurrence of paroxysmal supraventricular tachycardia New-onset supraventricular tachyarrhythmia

Data from Berns E, Rinkenberger RL, Jeang M, et al: Clinical efficacy and safety of flecainide acetate in the treatment of primary atrial tachycardias. Am J Cardiol 59:1337-1341, 1987.

OCCURRENCE OF VENTRICULAR PROARRHYTHMIA IN SUPRAVENTRICULAR TACHYCARDIA PATIENTS

The incidence of ventricular proarrhythmia in supraventricular tachycardia patients without structural heart disease has been low (<3%).4,6, 12, 15,16, 57 Stress testing', l5 may unmask some class IC wide QRS tachycardias in these patients; however, 1:l atrial flutter with aberrant conduction needs to be excluded (see Fig. 4).39Coplen et all2performed a meta-analysis of six studies using quinidine for atrial fibrillation. Of concern, quinidine was associated with a higher mortality, suggesting a possible ventricular proarrhythmia as a cause of death in several patients. Flaker et all6noted that atrial fibrillation patients with congestive heart failure who were treated with class IA agents had an increased mortality compared with congestive heart failure patients not treated with class IA agents. In atrial fibrillation patients with no congestive heart failure, however, the use of class IA agents did not affect survival. INCIDENCE OF VENTRICULAR PROARRHYTHMIA

Podrid et a P retrospectively analyzed 400 patients with 1287 single drug studies using noninvasive ECG. Aggravation of arrhythmia oc-

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curred in 117 patients (9%).In a study by Stanton et a1,58506 consecutive patients who underwent 1260 antiarrhythmic drug trials for VT or VF were reviewed for the incidence of proarrhythmia. Arrhythmogenic effects occurred in 6.9% of patients and 3.4% of drug trials. The incidence ranged from 11.8% caused by encainide to 0 occurring with procainamide, tocainide, or P-blockers. Arrhythmogenic effects more likely were seen when decreased systolic function measured by echocardiography at the base of the left ventricle was noted. In this study, proarrhythmia occurred after a mean of 4.9 ? 3.8 days in 8 of 162 patients taking propafenone; 1 of 25, flecainide; 10 of 56, amiodarone; 1of 79, mexiletine; 1 of 95, disopyramide; and 1 of 167, quinidine. Arrhythmogenic effects occurred in 10.3% of sustained VT patients, 6.8% of nonsustained VT patients, and 2.3% of VF patients ( P = .02). Reports of the incidence of proarrhythmia with individual drugs are published in the literature. With encainide, 11%to 28% of patients with a baseline history of sustained VT develop a proarrhythmic res~onse.'~, 42, 56, In patients with PVCs, however, only a 2% incidence was noted.62With flecainide, in patients with a history of sustained VT or VF, Reid et ar7 reported development of incessant VT or VF, which could not be terminated with cardioversion, in 19%. However, La1 et al,27 in a group of 38 patients with sustained VT or VF, noted the development of true proarrhythmia only in 4 patients (10%). The occurrence of spontaneous proarrhythmia with mexiletine is low. In a study by Berns et a1,5 56 patients with sustained VT treated with mexiletine did not have a single incidence of spontaneously occurring proarrhythmia. Moricizine has been noted to have about a 4% incidence of proarrhythmia.34,M Fewer than 10% of patients in the moricizine database had a clinical history of sustained VT, however. Although amiodarone causes serious ventricular proarrhythmia only in 1%to 2% of patients, drug-induced torsades de pointes can occur in 5% of patients treated with sotalol or dofetilide if not dosed appropriately. Incidence of Proarrhythmic Effects-lnvasive Electrophysiology Criteria

If electrophysiology testing is used to evaluate drug effect, the incidence of drug-induced arrhythmia is higher. This higher incidence may be secondary to the fact that the criteria for proarrhythmia are too liberal. In a study by Poser et al,43 63 patients underwent 216 electrophysiology studies. Arrhythmia aggravation occurred in 19 of the 63 patients (30%).Arrhythmia aggravation in the electrophysiology laboratory ranged from' 5% with tocainide and disopyramide to 36% with encainide. Horowitz et all9reported on 160 patients who underwent 432 drug trials. Arrhythmia aggravation occurred in 68 studies (16%) and in 51 patients (32%).In 17% of these patients, nonsustained VT was converted to sustained VT; in 12'30, VT was induced more easily; and in 59'0,

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hemodynamically stable VT became unstable, requiring cardioversion. Using these criteria, Horowitz et all9 noted a 5% to 7% proarrhythmic response during monotherapy testing with procainamide, quinidine, mexiletine, and amiodarone. Rae et a1& studied 314 patients undergoing 801 drug studies with nonsustained VT, sustained VT, or VF at presentation. Proarrhythmia occurred with each of 14 drugs evaluated in 24% of drug trials. The proarrhythmic rate was only 8% if more rigorous criteria of proarrhythmia were used, however. Class IC agents had the highest incidence of proarrhythmia. There was no significant difference in incidence of proarrhythmia in patients who received drug combinations compared with single drug regimens, and proarrhythmia with one agent did not predict arrhythmia exacerbation with another drug. Except for quinidine (Q-T slightly longer in proarrhythmic group), serum drug concentrations did not correlate with proarrhythmia or with surface ECG changes. Proarrhythmia was more common in patients with reduced left ventricular ejection fractions. A few other reports of proarrhythmia occurring during electrophysiology testing exist. Rinkenberger et a P reported that nonsustained VT was converted to sustained VT in 11 of 83 patients (13%)during electrophysiology evaluation of disopyramide, quinidine, and amiodarone. Staves et a159reported that 3 of 16 patients (19%)treated with propafenone developed incessant VT during electrophysiology testing. In a review of the flecainide database, Morganroth and H o r o ~ i t zreported ~~ that arrhythmia aggravation occurred in 30 of 254 patients (12%overall) who underwent electrophysiology testing. Incidence of Ventricular Proarrhythmia with Class IC Agents

Studies of proarrhythmia have shown that patients with more malignant arrhythmias and organic heart disease and left ventricular dysfunction have a higher incidence of new-onset sustained or incessant VT. Winkle et aP2 reported that encainide caused arrhythmia worsening in 11% of patients with a history of sustained VT or VF compared with only 2% in patients treated for PVCs. In an extensive review of the flecainide database, 12% of 254 patients with sustained VT developed proarrhythmia, whereas only 4% of 334 patients receiving therapy for In an update of PVCs or nonsustained VT developed pr~arrhythmia.~~ these initial findings, Morganroth et aP1 reported the incidence of flecainide proarrhythmia was 2.8% in patients presenting with arrhythmias, PVCs, and nonsustained VT versus 16.4% in patients presenting with VT or VF. In the flecainide database (Table l),3.5% of patients without structural heart disease had arrhythmia aggravation compared with 7.4% with structural heart disease. With encainide, the incidence was 2.8% and 9.6%.Although proarrhythmia is frequent with these drugs in highrisk patients, a lethal proarrhythmia is rare, occurring in only 1.2% of the flecainide database.

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Table 1. FREQUENCY OF PROARRHYTHMIA AND DEATH FROM PROARRHYTHMIA WITH FLECAINIDE

PVC

No structural heart disease Proarrhythmia 4/132 (3%) Death 0/132 ( O n ) Structural heart disease Proarrhythmia 4/338 (1.2%) 0/338 (0%) Death

NSVT

SVT

Total

2/64 (3.1%) 0/64 (0%)

2/28 (7.1%) 0/28 (0%)

8/224 (3.6%) 0/224 (0%)

16/405 (4.0%) 1/405 (0.2%)

62/363 (17.1%) 12/363 (3.3%)

82/1106 (7.4%) 13/1106 (0.2%)

PVC = Premature ventricular contraction; NSVT sustained ventricular tachycardia.

=

nonsustained ventricular tachycardia; SVT =

PROARRHYTHMIA AS A MECHANISM OF ENHANCED MORTALITY IN THE CARDIAC ARRHYTHMIA SUPPRESSION TRIAL

Encainide and flecainide were associated with 3.5 increased risk of sudden cardiac death compared with placebo in the Cardiac Arrhythmia Suppression Trial (CAST)." Although not well defined, constant enhanced mortality over the entire follow-up period may be secondary to a late-occurring proarrhythmia. The combination of antiarrhythmic drugs slowing ventricular conduction, associated myocardial ischemia, and changes of autonomic tone may have reared a significant arrhythmogenic milieu. Although encainide and flecainide appear to enhance mortality in the post-myocardial infarction setting, extrapolation of this database to the chronic setting is not justified. The addition of P-blockers to class IC drugs in this trial appeared to provide a protective effect because the incidence of death was similar to the placebo group. In the chronic setting, proarrhythmic data have been well studied with encainide and flecainide. Pritchett and Wilkinson" showed no excess mortality of encainide-treated or flecainide-treated SVT patients compared with a Duke population SVT control group. The Cardiac Arrhythmia Pilot Study (CAPS)" was associated with a low incidence of spontaneous proarrhythmia, varying from 3% to 7% based on ECG criteria. Because of spontaneous variability and defined proarrhythmic criteria, placebo patients had a 3% incidence of proarrhythmia. In the post-myocardial infarction setting, the CAST data suggest that encainide and flecainide should not be used in a CAST-type patient. P-Blockers, including timolol, propranolol, metoprolol, and acebutolol, reduce mortality in this ~etting.3~ Sotalol, a P-blocker with class I11 effects, did not reduce mortality statistically in this setting, however?2 Well-controlled post-myocardial infarction data do not exist for the class IA and IB antiarrhythmic drugs?* Although propafenone has many properties similar to flecainide and encainide, it differs in its basic electrophysiology by having different onset and offset kinetics and some P-blocking properties. Dofetilide in the DIAMOND tria160 and amiodarone in the EMIATZ1and CAMIAT'O trials had no adverse effects on mortality, and

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these class I11 agents are safe to use in the post-myocardial infarction setting. PREDICTORS OF ARRHYTHMIA AGGRAVATION

Although proarrhythmia occurs frequently, the exact cellular mechanisms for this complication are not known. Cellular mechanisms may be related to binding and dissociation rates of drugs to the sodium channel membrane. Most studies in the literature have not identified clinical characteristics that would predict the patients at risk for proarrhythmia. Although torsade de pointes with class IA agents usually are associated with prolongation of the Q-T interval, no other ECG changes, including QRS prolongation, or blood levels (about 50% of patients have subtherapeutic blood levels) have been found to predict the development of this proarrhythmia. Many patients who develop torsade de pointes have baseline Q-T prolongation. Class IA-induced torsade de pointes appears to be more likely to occur in the setting of hypokalemia, hypomagnesemia, and bradycardia (e.g., heart block). Although quinidine-induced torsade de pointes may be idiosyncratic and not dose dependent, sotalol at doses greater than 320 mg/d, dofetilide at higher doses, and procainamide (when N = acetylated procainamide levels are > 20 to 40 Fg/mL) appear to have a dose relationship. Reports from the literature suggest that half of the episodes of torsade de pointes during quinidine therapy occur in atrial fibrillation patients. The atrial fibrillation may be a marker of organic heart disease, and long-short sequences may make it more likely to initiate early after-depolarizations that are mechanistic in the development of this proarrhythmia. Morganroth and H o r o ~ i t rez~~ ported that the risk of quinidine-induced torsade de pointes is low in patients receiving the drug for symptomatic benign or potentially lethal ventricular arrhythmias in which hypokalemia, digitalis toxicity, or Q-T intervals greater than 0.5 second were absent. Although not well studied, reportsz0exist of some crossover effect in which a patient who developed torsade de pointes on one drug would have an increased risk of the same if exposed to another similar drug. Class IC drugs frequently cause prolongation of the P-R and QRS intervals. The occurrence of these conduction abnormalities has not been associated with a higher incidence of class IC-induced ventricular proarrhythmia. High drug doses with toxic levels (flecainide) and rapid dose escalations are associated with a higher incidence of proarrhythmia, however. Stress testing by adrenergic mechanisms or by rest-dependent mechanisms may unmask class IC-induced sustained VT.', l5 Box 4 lists some risk factors associated with the occurrence of other forms of ventricular proarrhythmia. Age, sex, cardiac diagnosis, occurrence of other side effects, and location of prior infarction do not predict proarrhythmia. No firm data exist to show that proarrhythmia caused by one antiarrhythmic drug predicts accurately that a proarrhythmia would occur with another antiarrhythmic drug, even a drug in the same subclass. Despite this lack of relationship, it is advisable to proceed

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more cautiously in patients who previously have had a significant proarrhythmia when initiating new drug therapy. Medications that cause a proarrhythmia when used alone may not do so when used in combination. Rae et a146noted that 55% of patients treated with drug combinations did not exhibit a proarrhythmia despite using prior drugs that when used alone were associated with a proarrhythmia response. Structural heart disease Left ventricular dysfunction History of sustained ventricular tachyarrhythmia Early post-myocardial infarction period (ischemia) Slater et a155studied 51 patients who developed proarrhythmia on encainide, mexiletine, or quinidine and compared them with 102 patients who did not experience any proarrhythmia with these three drugs. Analysis of age, sex, presenting arrhythmia, nature of the underlying heart disease, left ventricular dysfunction, ischemia, ECG intervals at baseline and during therapy, density of arrhythmia on control monitor and stress test, average drug doses, and drug blood levels were compared. The only two variables associated with arrhythmia aggravation were the nature of the presenting arrhythmia and left ventricular function and left ventricular ejection fraction. Patients presenting with sustained VT or VF had a significantly greater incidence of this complication compared with patients presenting with nonsustained VT or PVCs with an odds ratio of 3.9 ( P = .01). The average ejection fraction in patients with proarrhythmia was 37% compared with 43% in patients without worsening (P = .8). In the group with an ejection fraction less than 35%, however, there was a greater incidence of aggravation when compared with the group with an ejection fraction greater than 35% with an odds ratio of 2.5:l (P= .04). None of the other variables correlated with this drug-induced arrhythmia. Worsening of arrhythmia with one drug did not predict aggravation with any other drug. Of 16 patients who had arrhythmic aggravation on quinidine, 14 had received disopyramide or procainamide, and only 1 patient had arrhythmia worsening with these latter two agents. Although mexiletine caused arrhythmia aggravation in 13 patients, only 3 developed proarrhythmia on tocainide. Of 22 patients who had aggravation with encainide, only 4 of 16 developed proarrhythmia on flecainide. One third of the aforementioned patients developed arrhythmia aggravation only during exercise stress testing, which may be especially important in patients treated with class IC agents. In the post-myocardial infarction setting, ischemia probably plays a 22, 23 The combinasignificant role in the occurrence of pr~arrhythmia.'~, tion of antiarrhythmic drug-induced conduction slowing with myocardial ischemia and some autonomic changes probably represents a highrisk proarrhythmic environment. Digitalis toxic arrhythmias are dose and serum concentration dependent.55Digitalis-induced rhythm disorders are more likely to occur in the setting of inadvertent overdose, such as in the setting of renal failure and decreased clearance of parent compound.

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PHARMACOKINETIC CAUSES OF ARRHYTHMOGENESIS

The development of proarrhythmia often is idiosyncratic. Some episodes of arrhythmia aggravation are antiarrhythmic dose related, however. Early dose escalations before a drug or metabolite reaches steady-state may lead to toxic levels. Decreases in drug clearance can lead to increased plasma concentrations of antiarrhythmic drugs and cause pr~arrhythmia.~~ For example, drugs that are metabolized extensively by the liver may be affected in patients with congestive hepatomegaly, alcoholic-induced hepatitis, or alterations in hepatic metabolism secondary to concomitant medications. In patients with renal failure, drugs that are cleared renally (sotalol, defetilide) may be associated with toxic levels of the parent compound. Buildup of active metabolites, such as N-acetylated procainamide, may be arrhythmogenic. In most cases, protein binding is constant over the range of clinical doses used. Several drugs, including disopyramide and propafenone, have nonlinear protein binding, however. In this situation, the fraction of drug in plasma (not bound to protein) increases at higher drug concentrations and doses. Higher doses may result in marked increases in plasma concentrations that are not linear to the increase in dose. In rare situations, this increase in plasma concentration may lead to inadvertent toxic doses that may cause a proarrhythmic response. Although drugs in the same class and subclass have similar properties, differences in basic electrophysiologiceffects, onset and offset kinetics, active metabolites, and effects on ischemic tissue suggest that no two drugs are 51 It is not surprising that a proarrhythmia occurring on one drug is not predictive of a proarrhythmia occurring on another antiarrhythmic drug. Au et a12 studied the proarrhythmic effects of several class IA agents using programmed electric stimulation. During 55 drug trials in 24 patients, 6 patients had a proarrhythmic response. A proarrhythmic response to one drug did not predict a similar response to another class IA drug. Drug interactions may increase the likelihood of proarrhythmia. Amiodarone increases significantly blood levels of class IA agents and flecainide when used con~omitantly.~~ Toxic class IA serum concentrations may prolong repolarization further and cause torsades de pointes. Additive electrophysiology effects of concomitantly used drugs may cause arrhythmogenic effects, such as slowing of myocardial conduction prolongation of repolarization or drug-induced bradyarrhythmias. INPATIENT VERSUS OUTPATIENT INITIATION OF ANTIARRHYTHMIC DRUGS

Initiation of class IA, 111, and IC drugs is associated with a small incidence of drug-induced proarrhythmia. Because of this association, outpatient initiation of these drugs may put some patients at risk for a

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life-threatening proarrhythmia. By observing patients on telemetry, early proarrhythmic effects can be identified. Maisel et alZ8noted a 7.9% incidence of bradycardic proarrhythmia and 1.3% incidence of ventricular proarrhythmia in a group of inpatients treated with various antiartorsades de rhythmics for atrial fibrillation. In the DIAMOND pointes was noted in 25 patients (3.3%) treated with dofetilide. Because all cases were observed under telemetry conditions, only 2 patients died. Three fourths of these cases were observed within 3 days of initiation of treatment. With all antiarrhythmics, 30% to 50% of proarrhythmias can occur after this telemetry period, however. Inpatient telemetry does not capture all proarrhythmic events. As an alternative to admitting all patients treated with antiarrhythmics, the authors do the following in their practice. All patients with a history of sustained VT or VF are monitored closely in telemetry beds in the hospital during active drug titration. In patients with nonsustained VT, high-risk patients are admitted to telemetry beds (see Box 5). In patients at low risk for proarrhythmia (benign, symptomatic PVCs) whom it is preferable to treat in the outpatient setting, drugs with a low proarrhythmic profile, such as mexiletine and @-blockers(see Box 6), or a low risk of torsades de pointes, such as flecainide or propafenone, are used predominantly. Amiodarone has a relatively low incidence of spontaneous proarrhythmia. In patients with sustained VT or VF, amiodarone therapy is initiated as an inpatient. In patients with atrial fibrillation, amiodarone usually is initiated as an outpatient, given its low incidence of causing ventricular proarrhythmia in this group of patients. Use of antiarrhythmic drug combinations, such as @-blockers and class I agents or class IA and IB agents, may minimize some of the proarrhythmic effects noted with larger doses of class IA agents alone. In patients with idiopathic atrial fibrillation, flecainide and propafenone can be initiated safely as an outpatient. The predominant class ICinduced proarrhythmia is 1:l atrial flutter. Table 2 presents the authors’ approach for initiating outpatient versus inpatient antiarrhythmic therapy.

Table 2. INPATIENT VERSUS OUTPATIENT INITIATION OF ANTIARRHYTHMIC DRUGS FOR ATRIAL FIBRILLATION OR BENIGN VENTRICULAR ARRHYTHMIA In Atrial Fibrillation Hospital

IA IC* Sotalol/ dofetilide Amiodarone *No structural heart disease. RC = Rate control.

Outpatient

.x X

In Normal Sinus Rhythm Hospital

Outpatient

X

x (RC) X

X

X (RC)

X

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High-Risk Patients With Nonsustained Ventricular Tachycardia Best Hospitalized for Safe Antiarrhythmic Therapy Left ventricular dysfunction Coexisting atrial fibrillation if type IA therapy considered Prior antiarrhythmic drug failures Prior proarrhythmic response Baseline prolonged Q-T interval Baseline conduction abnormalities Sinus node dysfunction Bundle-branch block Elderly patients Hepatic or renal dysfunction Abnormal signal-averaged electrocardiogram

Procedures to Minimize Risk of Outpatient Antiarrhythmic Therapy 1. Use drugs with low incidence of proarrhythmia as first-line therapy a. p-blockers b. Class 1B agents-mexiletine, tocainide c. Class IC agents if no structural heart disease d. Amiodarone 2. Minimize initiating outpatient therapy with type IA drugs that can cause torsades de pointes 3. Do not initiate class IA or Ill therapy as outpatient if concomitant atrial fibrillation 4. Consider admission of high-risk patients 5. If initiating class IA or Ill agents, observe for several hours postconversion of atrial fibrillation, check Q-T 6. Use event recorders to monitor outpatient titration of antiarrhythmic drugs

Avoiding proarrhythmia is the best treatment. A careful knowledge of the antiarrhythmic drugs, their pharmacokinetics, their negative isotropic abilities, their electrophysiologic effects, and their known incidence of causing proarrhythmia in various patient subtypes is useful in minimizing the occurrence of proarrhythmia. For example, in patients with sustained VT and an ejection fraction less than 30%, flecainide would cause a proarrhythmia in greater than 10% of patients. In similar patients, mexiletine or amiodarone would cause a proarrhythmia in less than 3%. The first step in the treatment of a patient with a proarrhythmia is to make the diagnosis. Early recognition may minimize the severity of the proarrhythmia because the offending agent can be discontinued quickly. Although it is sometimes difficult to differentiate antiarrhythmic

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inefficacy from proarrhythmia, it is best to consider this situation to be a proarrhythmia and switch antiarrhythmic therapy. Although this approach results in the rare discontinuation of a drug that may be effective at higher doses, it avoidsfeeding the fire with higher doses of an offending agent. Treatment of new-onset sustained VT (without a prolonged Q-T) includes withdrawing the offending agent and administering intravenous antiarrhythmics with a low incidence of proarrhythmia (lidocaine, amiodarone), if necessary. Cardioversion with defibrillation and cardiopulmonary resuscitation may be needed in patients with hemodynamically unstable, incessant tachycardia. In patients who have incessant, hemodynamically stable VT, discontinuation of the offending agent with continuous ECG monitoring is mandatory. As antiarrhythmic blood levels decrease, the tachycardia rate increases. Usually at this point, pacing termination or cardioversion is successful. The use of propranolol has been advocated in some cases of class IC-induced VT.36 In patients who develop torsades de pointes associated with prolonged Q-T interval, the offending agent should be discontinued. Serum potassium and magnesium levels should be checked. Early recognition of frequent long pauses followed by U waves and short runs of polymorphic VT often precede the development of sustained torsade de pointes. Early discontinuation of the causative agent may avoid the occurrence of sustained VT. Correction of electrolyte abnormalities is crucial. Magnesium sulfate can be given intraven~usly.~ Drugs that prolong the Q-T interval further, such as quinidine and procainamide, should be avoided. If necessary, drugs such as lidocaine, tocainide, mexiletine, propranolol, and phenytoin, which shorten the Q-T interval, may be useful. Electrolyte abnormalities, hypoxia, and acidosis should be corrected. Isoprotereno1 can be administered acutely to increase the rate and avoid pauses. This approach often shortens the Q-T interval and presumably reduces the temporal dispersion of repolarization. If isoproterenol is ineffective, temporary pacing at rates of 80 to 110 beats/min can be performed to overdrive suppressed arrhythmia and prevent pauses. Treatment of digitalis-induced VT includes discontinuing digitalis therapy; maintaining serum potassium levels in the high therapeutic range; and treating with lidocaine, phenytoin, or propranolol and digoxin-immune Fab fragments if necessary. If the proarrhythmic event is symptomatic bradycardia, such as sinus bradycardia, sinoatrial exit block, sinus arrest, or AV block, atropine or isoproterenol or temporary cardiac pacing can be used during withdrawal of the offending agent. In patients who develop drug-induced atrial proarrhythmia, such as atrial tachycardia with block from digitalis, the usual treatment is withholding digitalis. If symptomatic tachycardia exists, digitalis antibody treatment or temporary pacing may be useful. In patients who develop more frequent but slower supraventricular tachycardia, discontinuation of the offending agent is the best treatment. Recurrences can be treated with vagal maneuvers, intravenous verapamil, or adenosine. In some cases, temporary antitachycardia pacing is useful. In patients who develop 1:l atrial flutter,

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discontinuation of the offending agent often may be useful. AV nodeblocking agents, such as digitalis, verapamil, or P-blockers, may help in rate control until effective therapy can be attained. Ablation of atrial flutter and continuing the drug for suppression of paroxysmal atrial fibrillation has been effective in such patients. CONCLUSIONS Antiarrhythmic drugs often are useful in treating patients with various arrhythmic syndromes. Although proarrhythmia can occur with many agents, most proarrhythmia is not life-threatening. The incidence of proarrhythmia can be minimized if one has a careful understanding of the electrophysiologic effects, pharmacokinetics, and proarrhythmic profiles of the various antiarrhythmic agents. Avoidance is the best treatment. In patients who develop proarrhythmia, early recognition is mandatory. In-hospital monitoring of patients believed to be at high risk for a proarrhythmia is mandatory. In the outpatient setting, the use of drugs with low proarrhythmic profiles minimizes any nonmonitored occurrence of significant proarrhythmia. References 1. Anastasiou-Nana MI, Anderson JL, Stewart JR, et al: Occurrence of exercise-induced and spontaneous wide complex tachycardia during therapy with flecainide for complex ventricular arrhythmias: A possible proarrhythmic effect. Am Heart J 113:1071-1072, 1987 2. Au PK, Bhandari AK, Bream R, et al: Proarrhythmic effects of antiarrhythmic drugs during tachycardia. J Am Coll Cardiol 9:389-397, 1987 3. Banai S, Tzivoni D: Drug therapy for torsade de pointes. J Cardiovasc Electrophysiol 4206-210, 1993 4. Benditt DG, Bailin S, Remole S, et a1 Proarrhythmia: Recognition of patients at risk. J Cardiovasc Electrophysiol 2:5221-5232, 1991 5. Bems E, Naccarelli GV, Doughetty AH, et al: Mexiletine: Lack of predictors of clinical response in patients treated for life-threatening tachyarrhythmias. J Electrophysiol 2:201-206, 1988 6. Bems E, Rinkenberger RL, Jeang M, et al: Clinical efficacy and safety of flecainide acetate in the treatment of primary atrial tachycardias. Am J Cardiol59:1337-1341,1987 7. Bigger JT, Sahar D I Clinical types of proarrhythmic response to antiarrhythmic drugs. Am J Cardiol59:2E-9E, 1987 8. Brown MA, Smith WM, Lubbe WF, et al: Amiodarone-induced torsade-de-pointes. Eur Heart J 7234-239, 1986 9. Buxton AE, Lee KL, Fisher JD, et al: for the Multicenter Unsustained Tachycardia Trial Investigators: A randomized study of the prevention of sudden death in patients with coronary artery disease. N Engl J Med 341:1882-1890, 1999 10. Caims JA, Connolly SJ, Roberts R, et a1 for the Canadian Amiodarone Myocardial Infarction Arrhythmia Trial Investigators: Randomized trial of outcome after myocardial infarction in patients with frequent or repetitive ventricular premature depolarisations. CAMIAT. Lancet 349:675482,1997 11. CAPS Investigators: Effects of encainide, flecainide, imipramine and moricizine on ventricular arrhythmias during the year after acute myocardial infarction. The Cardiac Arrhythmia Pilot Study. Am J Cardiol61:501-509, 1988

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12. Coplen SE, Antman EM, Bedin JA, et a1 Efficacy and safety of quinidine therapy for maintenance of sinus rhythm after cardioversion: A meta-analysis of randomized controlled trials. Circulation 82:11061116, 1990 13. Dessertenne F: La tachycardic ventriculaire a deux foyers opposes variables. Arch Mae Coeur Vaiss 59:26>272, 1966 14. Echt DS, Liebson PR, Mitchell LB et al, and the CAST Investigators: Mortality and morbidity in patients receiving encainide, flecainide, or placebo: The Cardiac Arrhythmia Suppression Trial. N Engl J Med 324:781-788, 1991 15. Falk RH: Flecainide-induced ventricular tachycardia and fibrillation in patients treated for atrial fibrillation. Ann Intern Med 11:107-111, 1989 16. Flaker GC, Blackshear JL, McBride R, et al: Antiarrhythmic drug therapy and cardiac mortality in atrial fibrillation. J Am Coll Cardiol 20:527-532, 1992 17. Herre JM, Titus C, Oeff M, et al: Inefficacy and proarrhythmic effects of flecainide and encainide for sustained ventricular tachycardia and ventricular fibrillation. Ann Intern Med 113:671-676, 1990 18. Hohnsloser SH, Van de Loo A, Baedeker F: Efficacy and proarrhythmic hazards of pharmacologic cardioversion of atrial fibrillation: Prospective comparison of sotalol versus quinidine. J Am Coll Cardiol26:852-858, 1995 19. Horowitz LN, Greenspan AM, Rae AP, et al: Proarrhythmic response during electrophysiologic testing. Am J Cardiol 59:45E48E, 1987 20. Jackman WM, Friday KJ, Anderson JL, et al: The long QT syndromes: A critical review, new clinical observations and a unifying hypothesis. Prog Cardiovasc Dis 31:115-172, 1988 21. Julian DG, Camm AJ, Franglin G, et a1 for the European Myocardial Infarct Amiodarone Trial Investigators: Randomized trial of effect of amiodarone on mortality in patients with left-ventricular dysfunction after recent myocardial infarction. EMIAT. Lancet 349:667-674, 1997 22. Julian DG, Prescott RJ, Jackson FS, et al: Controlled trial of sotalol for one year after myocardial infarction. Lancet 1:1142-1147, 1982 23. Kennedy H L Late proarrhythmia and understanding the time of occurrence of proarrhythmia. Am J Cardiol661139-1143,1990 24. Kowey PR, Vanderlugt J, Luderer J R Safety and risk/benefit of ibutilide for acute conversion of atrial fibrillation/flutter. Am J Cardiol784652, 1996 25. Kuck KH, Kunze KP, Roewer N, et al: Sotalol-induced torsade-de-pointes. Am Heart 1 107179-180, 1984 26. Kutalek SP. McCormick DT. Porter RS: The conceut of uroarrhvthmia. In Naccarelli GV (ed): Clinical Cardiovascular Therapeutics: CGdiac' A r r h y k a s : A Practical Approach. Mt Kisco, NY, Futura, 1991, pp 397-412 27. La1 R, Chapman PD, Naccarelli GV, et al: Short and long-term experience of flecainide acetate in the management of refractory life-threatening ventricular arrhythmias. J Am Coll Cardiol6:772-779, 1985 28. Maisel WH, Kuntz KM, Reimold SC, et a1 Risk of initiating antiarrhythmic drug therapy for atrial fibrillation in patients admitted to a university hospital. Ann Intern Med 127:281-284,1997 29. Minardo JD, Heger JJ, Miles WM, et a1 Clinical characteristics of patients with ventricular fibrillation during antiarrhythmic drug therapy. N Engl J Med 319257-262, 1988 30. Morganroth J: Risk factors of the development of proarrhythmic events. Am J Cardiol 59:32E-37E3, 1987 31. Morganroth J, Anderson JL, Gentzkow GD: Classification by type of ventricular arrhythmia predicts frequency of adverse cardiac events from flecainide. J Am Coll Cardiol 8607415, 1986 32. Morganroth J, Horowitz L N Flecainide: Its proarrhythmic effect and expected changes in the surface electrocardiogram. Am J Cardiol5889&94B,1984 33. Morganroth J, Horowitz L N Incidence of proarrhythmic effects from quinidine in the outpatient treatment of benign or potentially lethal ventricular arrhythmias. Am J Cardiol 56:585-587, 1985 34. Morganroth J, Pratt CM: Prevalence and characteristics of proarrhythmia from moricizine. Am J Cardiol63:172-176, 1989

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mic drugs: A study of 506 patients treated for ventricular tachycardia or fibrillation. J Am Coll Cardiol 14:209-215, 1989 Staves CS, McGovem B, Grain H, et al: Aggravation of electrically provoked ventricular tachycardia during treatment with propafenone. Am Heart J 110:24-29, 1985 Torp-Pedersen C, Moller M, Bloch-Thomsen EB, et al, for the Danish Investigations of Arrhythmia and Mortality on Dofetilide Study Group: Dofetilide in patients with congestive heart failure and left ventricular dysfunction. N Engl J Med 341:8574365, 1999 Velebit V, Podrid P, Lown 8,et al: Aggravation and provocation of ventricular arrhythmias by antiarrhythmic drugs. Circulation 65:88@94, 1982 Friggin JC, et al: Malignant ventricular tachyarrhythmias Winkle RA, Mason JW, associated with the use of encainide. Am Heart J 102:857-864,1981 Woosley RL, Roden DM. Pharmacologic causes of arrhythmogenic actions of antiarrhythmic drugs. Am J Cardiol59:19E-Z5E, 1987

Address reprint requests to Gerald V. Naccarelli, MD Division of Cardiology Cardiovascular Center Penn State University College of Medicine The Milton S. Hershey Medical Center PO Box 20708; MC H047 500 University Drive Hershey, PA 17033