Amiodarone therapy in symptomatic, sustained refractory atrial and ventricular tachyarrhythmias

Amiodarone therapy sustained refractory tachyarrhythmias

in symptomatic, atria1 and ventricular

Amiodarone was utilized in 70 patients with symptomatic, sustained refractory tachyarrhythmias, Of these, 29 had atrial arrhythmia (20 recurrent atrial fibrillation and nine sustained supraventricular tachycardia). Control was achieved in eight with supraventricular tachycardia and in 16 with atrial fibrillation. Recurrence has been prevented in these 24 patients (83%) during an average follow-up of 63.4 months. An additional 41 patients had recurrent ventricular tachycardia. In 19 with symptoms consisting of dizziness or lightheadedness without syncope or clinically apparent hemodynamic compromise, treatment was limited to amiodarone. Of these, 14 responded (74%) and have been free of arrhythmia during an average follow-up of 13 months. In 22 who experienced either synco,pe or lifethreatening hemodynamic impairment, amiodarone was added to those agents which had only partially suppressed advanced grades of ventricular premature beats. Fourteen of these patients (64%) have remained free of recurrent ventricular arrhythmia during an average follow-up of 12 months. After drug loading, maintenance therapy consisted of a daily dose ranging from 200 to 600 mg. Only mild side effects have been encountered in the 17 patients (23%) with any untoward responses. This experience confirms that oral amiodarone is an effective and safely applied agent against recurrent refractory atrial tachyarrhythmia and sustained intractable ventricular tachycardia with moderate symptoms. While also efficacious in refractory sustained life-threatening ventricular tachyarrhythmia, usage of the agent is often difficult in this condition owing in part to insufficient information concerning amiodarone pharmacokinetics. (AM HEART J 101:374, 1981.)

Philip J. Podrid,

M.D., and Bernard

Lawn,

M.D. Boston,

Amiodarone, a benzofurane derivative, was developed as an antianginal agent and has found widespread application in Europe.‘. ’ Beneficial myoeardial hemodynamic effects result from decreased coronary vascular resistance and increased coronary blood flow.“. ’ Amiodarone also exerts noncompetitive beta-adrenoceptor blocking effects.4-6 Animal studies have shown significant antiarrhythmic properties as well.‘. * Preliminary clinical experience indicates utility for a variety of atria1 and ventricular tachyarrhythmiass-” Amiodarone is especially useful in controlling the supraventricular mechanisms associated with the Wolff-Parkinson-White (WPW) syndrome.‘2’ I3 Its unusually long half-life and infrequent side effects make it unique among antiarrhythmic drugs. A major limitation in clinical appli-

Mass.

cation is the lack of guidelines for therapeutic adequacy. This is due to the long time-course in onset of action and absence of blood level data to determine appropriate dosing. These deficiencies are especially perplexing when the taehyarrhythmia being treated is potentially life-threatening. For the past 3 years we have utilized amiodarone for both supraventricular and ventricular tachyarrhythmias refractory to conventional and, in some cases,investigational antiarrhythmic drugs of which this report constitutes our clinical experience. METHODS Patient population. The population studied consisted of 70 patients referred for management of recurrent tachyarrhythmias. There were 52 males and 18 females with an average age of 56 years (16 to 78 years). Cardiac diagnosis included coronary disease in 34 patients, cardio-

myopathy in five, WPW syndrome in three, and valvular From the Cardiovascular School of Public Health Women’s Hospital.

Laboratories, Department and the Cardiovascular

of Nutrition, Harvard Division, Brigham and

Supported in part by Grants No. HL-18783 and HL-07776 from National Heart, Lung and Blood Institute of the National Institutes Health, US Public Health Service, Bethesda, Md. Received Reprint School

374

for pubiication requests: of Public

Bernard Health,

Dec.

16, 1980;

Lawn,

M.D., 665 Huntington

accepted

Dec.

24, 1980.

Professor of Cardiology, Harvard Ave., Boston, MA 02115.

the of

disorders in three; no underlying heart disease was demonstrated in 25 patients. Based on the site of the arrhythmia, the population was divided into two groups. Group 1 consisted of 29 patients who had refractory atria1 rhythm disorders which had been recurrent for 1 to 61 years (average 9.9 years), including paroxysmal atria1 fibrillation (AF) in 20 and recurrent supraventricular tachycardia (SVT) in nine. In these with SVT, five bad daily 000%8703/81/040374

+ 06$00.60/00

1981 The C. V. Mosby Co.

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episodes, three ha.d arrhythmia weekly, and one had monthly recurrences. In the AF patients, the arrhythmia recurred daily in eight, weekly in :five, and monthly in seven. Group 2 consisted of 41 patients who had frequent episodes of sustained ventricular tachycardia (VT), 14 of whom experienced ventricular fibrillation (VF) as well. These ventricular arrhythmias had recurred over a period ranging from 2 months to 19 years (average 2.4 years). Associated symptomatology. In all 70 patients the tachyarrhythmia was symptomatic. In group 1, complaints included palpitations, lightheadedness, dizziness, fatigue and dyspnea. In group 2, VT resulted in dizziness, syncope or symptoms suggesting hemodynamic compromise. To be treated with amiodarone, the symptomatic atria1 or ventricular tachyarrhythmiq required fulfillment of the following three criteria: (1) ECG documentation, (2) recurrent episodes, and (3) response to conventional drugs proved ineffective, poorly tolerated or resulted in intolerable side effects. Previous antiarrhythmic therapy. Previous ant&rrhythmic therapy is listed in Table I. Each patient with atria1 tachyarrhythmia had been treated with at least three other drugs before resorting to amiodarone. Patients with VT had been treated with an average of six drugs prior to the institution of amiodarone, which was generally the last drug to be utilized when therapy with other agents was only partially successful or completely unsuccessful. Prior to initiating amiodarone, all patients had 24 to 48 hours of continuous ambulatory ECG monitoring, exercise tolerance testing, standard blood chemistries, thyroid function studies, and ophthalmologic evaluation including slit lamp examination. Amiodarone therapeutic regimen in atrial tachyarrhythmias. In grou~p 1 patients, the initial daily dose was 600 mg and after 1 week was reduced to 200 mg daily. If the atria1 arrhythmia recurred after the initial 2 weeks, the dose of amiodarone was increased to 400 mg daily. Two patients with AF and one with SVT were receiving another antiarrhythmic agent; these included proprano101, aprindine, and verapamil. Amiodarone was added because these agents merely reduced frequency of recurrence. If the parox:ysms continued after a total of 4 weeks of amiodarone therapy, the agent was considered unsuccessful. Since these patients had symptomatic arrhythmias, recurrence was easily judged. Amiodarone was successful when the arrhythmia was prevented for a minimum period of 4 months. If the arrhythmia recurred, but compared to pretreatment at longer intervals with episodes more abbreviated and self-terminating, amiodarone was considered partially effective. A special arrhythmia calendar was kept by each patient to permit ready tracking of drug efficacy. Amiodarone therapeutic regimen in VT, Group 2 patients were treated with two different dosage schedules. The initial 34 received 600 mg daily for 1 week and then 200 to 400 mg once daily. In order to achieve more rapid control of ectopy, the remaining seven patients received 1200 mg daily for 1 week and then 400 to 600 mg daily. Amiodarone therapy was instituted in these patients after

Amiodarone

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Table I. Previous u.nsuccessful antiarrhythmics in the 70 patients with symptomatic recurrent tachyarrhythmias treated with amiodarone Atria1 tachyarrhythmias &oup 1; N = 29)

Ventricular tachyarrhythmias (group 2; N = 41)

Quinidine

29

Diiopyramide

27 17 24 8

41 34 41 29 27 28 24 16

Procainamide Propranolol Aprindine Tocainide Mexiletine Phenytoin Pindolol Digoxin Verapamil Metoprolol

Bretylium Lorcainide Ethmozin Encainide

16 7 2 -

-

8 11 4 6 6

ail previously utilized drugs had proved ineffective in preventing recurrent VT. Group 2 was divided into two subgroups based on clinical features of VT. Group 2A consisted of 19 patients who lhad recurrent VT without syncope but associated with diziiness or lightheadedness. In these patients amiodarone was given as the sole antiarrhythmic agent, since the arrhythmia was not immediately life-threatening. When a dose of 400 mg daily did not prevent recurrence, another antiarrhythmic drug previously deemed of some benefit was added. Since the VT was sporadic, the target of therapy was the ventricular premature beats, ( VPBs) categorized according to the Lown grading system: Grade 0 = no VPBs; Grade 1A = < 30 VPBs per hour (less than 1 per minute); Grade 1B = < 30 VPBs per hour (occasionally > 1 Ijer minute); Grade 2 = > 30 VPBs per hour; Grade 3 = multiform VPBs; Grade 4A = VPBs as couplets; Grade 4B = VT; and Grade 5 = early cycle VPBs (Ron-T phenomenon). Criteria for efficacy were based on both exercise testing and continous ECG monitoring and included all of the following: (1) total elimination of VT (Grade 4B) and early VPBs (Grade 5); (2) > 90% reduction in frequency of couplets (Grade 4A); (3) > 50% decrease in frequency of VPBs (per 24 hours of monitoring and per exercise test); and (4) > 50% reduction in the number of monitoring hours with frequent VPBs (Grade

2). Group 2B consisted of 22 patients with a history of VF or VT with syncope. Because of the life-threatening nature of the arrhythmia, the absence of guidelines for adequate amiodarone dose and lack of information about onset of drug action, another antiarrhythmic agent demonstrated to be partially effective was maintained in conjunction with amiodarone.

Fig. 1. Amiodarone therapy in a patient with supraventricular tachycardia. Short bursts of supraventriccontrol day (left panel). After two weeks of ular tachycardia @VT) are present tbronghout the entire amiodarone therapy there is total elimination of SVT (right panel). AEA = atria1 ectopic activity.

failure to control the arrhythmia. The procedures for exercise testing and Bolter monitoring have been described previously.15-1T Blood chemistries and thyroid function tests, as well as ophthalmologic examinations, were repeated at &month intervals

41 WTIENTS

AM0

/ 19

22

RESULTS

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fIdi%iD

/ AM&ROM ONLY

\ O::ER DRUGS

A&&ONE

I

\

DZD

S:DE EFFECTS

0T:ER DRUGS

Fig. 2. Amiodarone treatment and response of 41 patients with ventricular tachycardia. Nineteen patients (group 2A) received only amiodarone and 22 patients (group 23) were receiving another antiarrhythmic drug.

Group 1 (Atrial tachyarrhythmias). Amiodarone was effective in preventing recurrent atria1 tachyarrhythmias in 24 of 29 patients (83%) (Fig. 1). Of the nine patients with supraventricular tachycardia, eight were controlled including two with the WPW syndrome. Sixteen of 20 patients (80%) with recurrent AF have remained free of this arrhythmia during an average follow-up period of 13.4 months ranging 4 to 40 months. Among the 24 with an effective response, in I6 the daily dose had been ZOO mg or 400 mg in eight patients; three of these patients were also receiving propranolol, aprindine, or verapamil. One patient with SV’F developed a rash after 6 days of amiodarone therapy requiring discontinuation of the drug. Four patients with AF discontinued amiodarone, two because of side effects

and two because of recurrent arrhythmia. Patients were seen in follow-up at 3- to 6- month intervals with repeat 24-hour ECG monitoring and exercise testing. At each visit an interim history of symptoms was obtained. If the patient reported symptoms suggesting possible recurrence, follow-up interval was shortened with more frequent ambulatory ECG monitoring and exercise testing to document the nature of symptoms and possible

Group 2 (Ventricular tachyarrhythmias). Of the 41 patients with ventricular tachyarrhythmia, in I9 (group 2A) amiodarone was their only antiarrhythmic, while in 22 another agent was also employed (group 2B) (Fig. 2). Fourteen patients in group 28 (74%) responded to amiodarone and have remained free of recurrent V% (Fig. 3). Fourteen of 22 group

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Amiodarone

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in refractory

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Fig. 3. Amiodarone therapy for ventricular tachyarrhythmia.

Prior to therapy frequent salvos of ventricular tachvcardia (VT) were present. After 2 months of amiodarone therapy, VT was totally abolished. -

2B patients (64%) have been free of recurrence while on amiodarone. Concomitant drug thera@y in this group is listed in Table II. Overall, 28 of 41 patients (68%) remained on amiodarone for an average of 12 months (2 to 41 months). Fourteen patients have been on amiodarone for over 1 year and seven for over 2 years. The daily dose utilized was 200 mg in 17, 400 mg in seven, and 600 mg in four patients. Ten patients (died while on amiodarone. In two amiodarone was the sole antiarrhythmic, while eight were receiving another drug as well. Six patients had sudden death, three died of progressive heart failure, and one patient succumbed to lupus pneumonitis resulting from procainamide. In the two patients who had died while receiving amiodarone as the only agent, fatality was sudden and occurred 2.5 years and 3 years after initiation of amiodarone therapy. Three other patients discontinued the drug after only 1 week of therapy because of visual symptoms. Side effects. Side effects occurred in 17 patients (24%). Six patients developed typical cornea1 microdepo&ts.“, I3 One patient demonstrated a maculopapular rash after 6 days of therapy. Three patients commented about increased skin sensitivity to sunlight. Five complained of headaches, two of whom were receiving .600 mg and three who were receiving 400 mg daily. Two patients developed hair loss, which resolved upon reduction in dose from 400 to 200 mg daily. Interaction with coumadin, resulting in an increase in prothrombin time, occurred in

Table II. Sustained life-threatening ventricular tachycardia (group 2B): Concomitant antiarrhythmics in the 14 patients successfullytreated by amiodarone Concomitant antiarrhythmic

Number patients*

Quinidine Procainamide

3 3 2 2 3 1 2 1

Disopyramide Phenytoin Tocainide Aprindine Mexiletine Encainide *Three

patients

received

two

of

additional

antiarrhythmics

with

amioda-

rone.

four patients, necessitating discontinuation coagulant therapy.

of anti-

DISCUSSION Unique electrophysiolagic properties. In the experimental animal, amiodarone has .been persuasively shown to possessantiarrhythmic proper&es. Lubbe et al.18 found that in dogs the drug raises VF threshold and decreasesthe frequency of ventricular tachyarrhythmias when administered intravenously before or during coronary artery ligation. Singh and Vaughan-Williams’” have noted that amiodarone protects against ouabain-induced VF. Amiodarone has also been demonstrated to prolong the action potential duration by delaying repolarization,‘3, 2o

378

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but unlike many other antiarrhythmic drugs, there is no effect on upstroke velocity of phase 0. Within the AV node and accessory pathway tissue, amiodarone lengthens the refractory period and slows conduction.?” z2 Efficacy in refractory atrial tachyarrhythmias. Clinical experience with amiodarone indicates effectiveness in patients with supraventricular tachyarrhythmias.“. lo. I2 However, it is unclear whether these patients had refractory arrhythmias In the largest series reported by Rosenbaum et al.,‘” only 38% of patients had received other drugs prior to amiodarone. We treated only patients refractory to conventional drugs. Thus, the 29 with atria1 tachyarrhythmias received an average of three drugs unsuccessfully before being treated witk amiodarone. Nevertheless, we observed a successful response rate of over 80%, not dissimilar to that reported by others.g-ll Efficacy in refractory VT. To date evaluation of the efficacy of amiodarone in ventricular tachyarrhythmias has been based on nonsystematically obtained ECG rhythm strips of brief duration and subjective data concerning patient symptomatology. Studies with these methods yielded an effectiveness rate for amiodarone ranging from 77% ts 88%.9.lo. ?j. ” In the 19 patients we studied with recurrent symptomatic VT but without syncope or cardiac dysfunction (group 2A), 14 responded (74%) and have been free of arrhythmia during follow-up. Of our remaining 22 patients with life-threatening recurrent VT (group 2B) who had partial suppression with another agent, amiodarone was effective in 64%. While it might be suggested that ascribing efhcacy to amiodarone is inappropriate in these instances of successful recurrent VT suppression, amiodarone was nevertheless the drug of last resort and was added only when all other antiarrhythmics employed proved inadequate to prevent recurrence. Rosenbaum et al.“’ reported suppression of recurrent VT in 77% of 44 patients. It should be noted, however, that in 25 of their patients (57%) the arrhythmia was of recent onset or documented only at the time of admission’O; thus it is not clear whether amiodarone was indeed therapeutic. By contrast, our patients had VT and/or VI? which had been recurrent over a period ranging from 2 months to 19 years and was refractory to an average of six drugs prior to institution of amiodarone. Prevention of sudden death in refractory VT. Of 41 patients with recurrent VT who were receiving amiodarone, 10 died (24%) during a 12-month follow-up period, and in six death was sudden (15%). Two of the sudden deaths occurred among patients with mildly symptomatic VT (group 2A), while fonr

were noted among patients experiencing malignant VT (group 2B). In patients similar to those in group 2B, the incidence of sudden death was 3% when VT appeared controlled by antiarrhythmics but was 43% when such drugs proved ineffective.‘5 The criteria for VT control in the previous reporP were identical for the present study. Since amiodarone was only administered when all other agents available for use had faiIed, one would have anticipated a 43% annual incidence of sudden fatality. It is hkely that the addition of amiodarone in this high-risk group accounted for the reduction of sudden death to 15%5. Relatively small incidence and nonserious side effects. We encountered a smaller incidence of si

effects than previously reported. Earlier cornmumcations have noted cornea1 deposits in over 90% of patients.g, lo Only six of our 70 patients (9%) demonstrated such deposits. This might be explained by the smaller doses employed, the use of artificial tears, or the short period of therapy. We have not observed thyroid dysfunction’“~ ” or blue-grey skin rash.‘” A number of patients have noted an increased sensitivity to sunlight and dose-related headaches. Controlling prothrombin time has proved difficult in those receiving coumadin; this particularly adverse effect has not been reported by others. Conclusions. Amiodarone is an attractive antiarrhythmic agent. Among favorable features are freedom from serious side effects and a long half-life of 20 to 40 days. The need to take the drug once daily in conducive to drug compliance. However, the successful use of amiodarone is sometimes perplexing, especially in those with life-threatening ventricular tachyarrhythmias unresponsive to other antiarrhythmics. Since sufficient clinical pharmacokinetic data are lacking, there is uncertainty as to what constitutes a therapeutic or toxic dose, and there is inadequate information about the time required for onset and dissipation of drug action. An assay for serum blood levels of amiodarone is not as yet available. Electrocardiographic changes induced by the agent are relatively infrequent. When tachyarrhythmia recurs it is often unclear whether such failure results from inadequate dosing, insufhcient time for the drug to achieve therapeutic concentrations, or drug failure. The lack of objective guidelines for amiodarone application necessitates long periods of observation, particularly when changes in dose appear required. In patients wit potentially malignant ventricular tachyarrhythmias, the relative inability to ascertain drug effectiveness constitutes a substantial difficulty in the utility of amiodarone and, perhaps, might even have

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been a factor in sudden death of six of the present 41 patients having sustained refractory ventricular tachycardia. On the other hand, in recurrent supraventricular tachyarrhythmias and in symptomatic nonlife-threatening recurrent ventricular tachyarrhythmias, amiodarone is clearly an important and safely employed adjunct to the currently available pharmacologic armamentarium. REFERENCES 1.

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Vastesaeger M, Gellot P, Rasson G: Etude clinique d’une nouvelle medication anti angoreuse. Acta Cardiol 22:483, 1967. Daubert C, Bourdonnic L, Joubril A, Kombela P, Pong JC, Gauffault J: Traitment des syndromes de manace rebelles de l’enfarctus du myocarde par d’amiodarone. Coeur Med Interne 17:421, 1978. CBte P, Bourassa MG, Delaye J, Janin A, Froment R, David P: Effects of amiodarone on cardiac and coronary hemodynamics and on myocardial metabolism in patients with coronary artery disease. Circulation 59:1165, 1979. Charlier R, Deltour G, Bautheir J, Chaillet F: Pharmacology of amiodarone-an antianginal drug with a new biological profile. Arzneim Forsch 18:1408, 1968. Polster P, Broekhaysen J: The adrenergic antagonism of amiodarone. Biochem Pharmacol 25:131, 1976. Charlier R: Cardiac actions in the dog of a new antagonist of adrenergic excitation which does not produce competitive blockade of adrenoceptors. Br J Pharmacol39:668, 1970. Charlier R, Delaunois G, Bauthier J, Deltour G: Richerches dans la series des benzofuranes. XI. Proprietes antiarrhythmique de’1 amiodarone. Cardiologia 54:83, 1969. Charlier R, Deltour G: Correction des arrhythmies experimentales par I’amiodarone. J Pharmacologia (Paris) 1:175, 1970. Wheeler PJ, Ingram DV, Puretz L, Chamberlain DA: Amiodarone in the treatment of refractory supraventricular and ventricular arrhythmia. Postgrad Med J 55:1, 1979. Rosenbaum MB, Chiali PA, Halpern MS, Nau GJ, Przybylski J, Levi R, Lazzari J, Elizari MV: Clinical efficacy of amiodarone as an antiarrhythmic agent. Am J Cardiol 38:934, 1976. Vastesaeger MM, Gillot PH, Van der Straeten P: L’effect anti arrhythmique del’amiodarone. Brux Med 51:99, 1971. Rosenbaum MB, Chiali PA, Ryba D, Elizari MV: Control of tachyarrhythmias associated with WPW syndrome by amiodarone hvdroclhloride. Am J Cardiol 34:215. 1974. Wellens HJJ, :Lie KI, Bar FW, Wesdrop JC, Dohmen HJ,

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