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Clinical efficacy of amiodarone in treatment of recurrent ventricular tachycardia and ventricular fibrillation
Clinical efficacy of amiodarone in treatment of recurrent ventricular tachycardia and ventricular fibrillation The clinical antiarrhythmic efficacy of amiodarone treatment was examined in 196 patients with recurrent ventricular tachycardia (VT) or ventricular fibrillation (VF) resistant to other antiarrhythmic drugs. Patients had received a mean of 4.4 -t 1.9 unsuccessful drug trials over a mean of 15.2 months prior to amiodarone treatment of recurrent VF in 57 patients; recurrent, sustained VT in 95 patients; and recurrent, nonsustained VT in 44 patients. Amiodarone dosage during the first 2 to 4 weeks of treatment was 800 to 1600 mg/day. During long-term follow-up, amiodarone dosage was reduced to 200 to 600 mg/day, based on the control of arrhythmia and patient tolerance. Electrophysiologic studies were performed prior to and after 2 or more weeks of amiodarone treatment. After a mean follow-up of 18.2 + 13.0 months, 126 (64%) of 196 patients continued successful treatment with amiodarone. At electrophysiologic study, amiodarone prevented VT induction in 13 patients, and although VT was induced in 101 patients, 80 patients continued treatment for 14.2 months without recurrence of spontaneous VT. Amiodarone treatment was discontinued because of recurrent VT in 22 patients, sudden cardiac death in 15 patients, adverse effects in 12 patients, and noncardiac death in 21 patients. In nine patients, recurrent VT/VF appeared related to amiodarone-induced exacerbation of arrhythmia. Pulmonary toxicity occurred in seven patients, and 19 patients developed blue skin discoloration. Other adverse effects were usually dosage related. In summary, amiodarone was a highly effective antiarrhythmic drug, but at the dosages employed, the risk of significant adverse effects warrants careful surveillance during treatment. (AM HEART J 106:887, 1983.)
James J. Heger, M.D., Eric N. Prystowsky, Indianapolis,
M.D., and Douglas P. Zipes, M.D.
Ind.
Amiodarone, approved for general clinical use in Europe and the United Kingdom and an investigational agent in the United States since 1977, has been demonstrated to be an effective antiarrhythmic agent for treating recurrent supraventricular and ventricular tachyarrhythmias.l-lo In our initial series of 45 patients, we reported that amiodarone was effective in preventing recurrent ventricular tachycardia (VT) and ventricular fibrillation (VF) in 67% of patients? Treatment was often successful despite the continued ability to induce VT at elec-
From the Krannert Indiana University Medical Center.
Institute of Cardiology, School of Medicine, and
Supported in part by the Herman C. Indiana; grants HL-06308 and HL-07182 and Blood Institute, National Institutes of Indiana Public Health Trust; Roudebush cal Center, Indianapolis; and a Grant-In-Aid Association, Indiana Affiliate, Inc.
Department the Veterans
of Medicine, Administration
Krannert Fund, Indianapolis, from the National Heart, Lung Health; the Attorney General of Veterans Administration Medifrom the American Heart
Reprint requests: James J. Heger, M.D., Krannert 1001 W. 10th St., Indianapolis, IN 46202.
Institute
of Cardiology,
trophysiologic study during amiodarone treatment. Adverse effects were common but usually did not limit treatment, although some patients had significant and life-threatening adverse effects. This report updates our experience with amiodarone in the long-term management of recurrent VT and VF. METHODS Patient population. The study population included 196 patients who began amiodarone treatment for recurrent VT or VF and who had at least 1 month of follow-up prior to December 31, 1982. Of these 196 patients, there were 154 men and 42 women aged 18 to 77 years (mean 56.2 + 11.7 years) at the time of entry to study. Ischemic heart diseasewaspresent in 129 patients, documented by coronary arteriography in 106 patients and by clinical history and electrocardiographic evidence of prior myocardial infarction in 23 patients. Thirty-five patients had idiopathic, dilated cardiomyopathy, defined as global left ventricular dysfunction in the presenceof normal coronary arteries. Two patients had hypertrophic, nonobstructive cardiomyopathy, and one patient had an isolated right ventricular cardiomyopathy consistent with right 887
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Heger, Prystowsky,
and Zipes
ventricular dysplasia. In three patients, cardiomyopathy was secondary to chronic systemic hypertension. Mitral valve prolapse was present in eight patients, and eight patients had other forms of valvular heart disease, including prosthetic mitral valve replacement in two, prosthetic aortic valve replacement in three, rheumatic mitral regurgitation in two, and combined mitral stenosis and regurgitation in one patient. Nine patients had no evidence of structural heart disease by cardiac catheterization, echocardiogram, or clinical examination and were classified as having primary electrical disease. One other patient had a secundum atria1 septal defect. The majority of patients had evidence of significant left ventricular dysfunction. Based on New York Heart Association criteria, 25 patients had functional class I disease, 112 functional class II, 54 functional class III, and five functional class IV, according to symptoms and signs of congestive heart failure. Arrhythmia history. Episodes of recurrent VT or VF had beenpresent from 1 to 156months (mean 15.2 + 21.5 months) before the beginning of amiodarone treatment. VT was defined as three or more consecutive premature ventricular complexes. Recurrent, sustained VT, defined as VT that produced syncope, required electrical cardioversion, or lasted longer than 30 seconds,waspresent in 95 patients. In 44 patients, recurrent VT was nonsustained. Fifty-seven patients had experienced one or episodesof cardiac arrest from VF, which required cardiopulmonary resuscitation. Each patient received from two to 10 (mean 4.4 + 1.9) drug trials prior to amiodarone treatment. Of 863 prior drug trials, 798 failed becauseof recurrence of VT or VF, and 105 patients required cardioversion or defibrillation during prior drug trials. Treatment protocol. All patients were hospitalized for at least the first 2 weeks of amiodarone treatment. At admission, all antiarrhythmic drugs were discontinued, and during hospitalization, cardiac rhythm wasmonitored continuously. Amiodarone was administered at a dosageof 800 mgl day, given as400 mg every 12hours, for 4 to 8 weeks.After the first 1 to 2 months of treatment, amiodarone dosage was gradually and progressively decreased at 3-month intervals to dosagesof 200to 600 mg/day. The timing and magnitude of dosagechangeswere also influenced by the control of VT and the presenceof symptomatic adverse effects. Patients who entered the investigation during the last 6 months of the study period received an initial amiodarone dose of 1600 mg/day for the first 2 weeks of treatment. The dosagewas then reduced to 800 mg/day, and the dosage guidelines described previously for outpatient therapy were followed. Antiarrhythmic efficacy of amiodarone during initial dosingwasassessed only after at least 7 days of treatment. If recurrent VF or sustained VT recurred and produced sudden cardiovascular collapseafter 7 days of treatment, amiodarone wasdiscontinued. If during the initial month of treatment there continued to be episodesof nonsus-
American
October, 1983 Heart Journal
tained or sustainedVT that were hemodynamically stable, amiodarone was continued at a higher dosage,up to 800 mglday, or a secondantiarrhythmic drug wasadded. The specific choice of a secondantiarrhythmic drug wasbased, when possible,on the individual patient’s responseto that drug during prior trials. In two patients who had recurrent VT during the first months of treatment, amiodarone dosage was progressively increased to 1800 and 2000 mg/day, for 2 and 4 months, respectively. Prior to amiodarone treatment a drug-free, control electrophysiologic study was performed in 115 patients according to a previously described protocol for programmed electrical stimulation of the heart.” In 101 of 115 patients in whom VT was induced at control study, and in another 17 patients who did not undergo a control study, electrophysiologicstudieswere performed after 2 or more weeksof amiodarone treatment. The results of the electrophysiologic study only influenced the decision to continue amiodarone or to add additional antiarrhythmic drugs if the VT induced during programmed electrical stimulation had a cycle length <350 msec.In 11 patients, antiarrhythmic drugs were added to amiodarone, based solely on the responseof VT induction during electrophysiologic study. The electrophysiologic study was then repeated in these patients while they received the drug combination. RESULTS Clinical
antiarrhythmic
efficacy.
During a mean fol-
(range 1 to 57 months), 126 (64%) of 196 patients continued to receive amiodarone treatment. These 126 patients included 35 (61% ) of 57 who had recurrent ventricular fibrillation, 59 (62%) of 95 who had recurrent, sustained ventricular tachycardia, and 32 (73 % ) of 44 who had recurrent, nonsustained VT. low-up
of 16.2 -t 13.0 months
The results after the initial month of amiodarone
treatment are outlined in Table I. Amiodarone treatment was discontinued because of recurrent, spontaneous VT or VF in 14 patients, VT induced during electrophysiologic study in two patients, adverse effects in two patients, and death from heart failure in one. Of the 73 patients who had recurrence of spontaneous VT or VF, amiodarone alone (eight patients) or with an additional antiarrhythmic drug (51 patients) was continued in 59 patients, and 35 of these were given amiodarone throughout the follow-
up period. The outcome of long-term amiodarone treatment in 177 patients is outlined in Table II. No recurrence of spontaneous VT or VF was evident in 139 patients, of whom 112 have continued long-term treatment. VT or VF recurred in 38 patients. Fifteen patients had sudden cardiac death after 1 to 43 months (mean 10.4 F 10.6 months) of treatment. Of
six patients
in whom amiodarone
was discontinued
Volume Number
Table
106 4, Part 2
Amiodarone
1 (n = 107) 2 (n = 73)
3 (n = 13)
Table
(n = 3)
Response No spontaneous VT or VF Recurrent spontaneous VT
Treatment or VF
Treatment change because VT induced electrophysiologic study Adverse side effects Death from congestive heart failure
089
at
Amiodarone Amiodarone Antiarrhythmic Amiodarone Antiarrhythmic Amiodarone Amiodarone Amiodarone
Number
continued continued alone added discontinued added discontinued discontinued discontinued
of
patients
107 8 51 14 11 2 2 1
II. Outcome of long-term treatment with amiodarone Group
Response
1 (n = 139)
No spontaneous VT or VF Adverse side effects Death from CHF Noncardiac death Recurrent VT or VF
2 (n = 38)
Sudden *Three
VT- VF
I. Outcome of initial treatment with amiodarone for 1 month in 196 patients Group
4
in recurrent
of these patients
cardiac
died from congestive
death
Treatment Amiodarone Amiondarone
continued discontinued
Amiodarone Amiodarone
continued discontinued
Number
of
patients
112 10 16 1 17’ 6 15
heart failure.
because of recurrent arrhythmia, two had cardiac arrest from polymorphic VT possibly related to amiodarone, one was resuscitated from recurrent spontaneous VF, and three had recurrence of sustained VT. Two of the latter three patients underwent left ventricular aneurysmectomy and endocardial resection, and the other four patients were given other antiarrhythmic drugs. In 17 patients, admiodarone treatment was continued despite recurrent arrhythmia during longterm follow-up. One patient, who had received a radiofrequency burst ventricular pacemaker to terminate recurrent VT, successfully used the device on four occasions during 22 months of follow-up. In one patient who had recurrent VF after 1 month of treatment, amiodarone was continued in conjunction with implantation of an automatic defibrillator. Antiarrhythmic drugs were added in five patients, and one patient received an atria1 demand pacemaker because recurrent VT occurred during periods of spontaneous sinus bradycardia. In the other nine patients, the dosage of amiodarone was temporarily increased in six patients and remained unchanged in three during long-term follow-up. During continued follow-up of these 17 patients, three patients died from congestive heart failure that antedated onset of admiodarone treatment, and 14 patients have continued amiodarone treatment. In 41 of 126 patients receiving long-term amiodarone treatment, antiarrhythmic drugs have been added to amiodarone: aprindine in 12, aprindine and
propranolol in one, quinidine in 10, encainide in six, disopyramide in five, mexiletine in two, mexiletine and propranolol in one, propranolol alone in two, procainamide in one, and propafenone in one. In no patient did a drug combination appear to result in exacerbation of either ventricular arrhythmia or congestive heart failure. During the course of treatment, amiodarone was discontinued in 12 patients because of noncardiac adverse effects: pulmonary toxicity in five patients, nausea and anorexia in four, tremor and ataxia in one, urinary retention in one, and hyperthyroidism in one. Electrophysiologic studies. Electrophysiologic studies were performed after at least 2 weeks of amiodarone treatment in 101 patients in whom VT was induced at control study and in 17 patients who did not undergo a control study. Of the 101 patients in whom serial electrophysiologic studies were performed, amiodarone was discontinued in two patients after induction of sustained VT. In 15 patients, including two who received amiodarone combined with quinidine because of spontaneous VT, amiodarone prevented VT induction at repeat electrophysiologic study. None of these 15 patients had recurrent VT during long-term amiodarone treatment. In the other 84 serially studied patients and in 17 patients who did not undergo a control electrophysiologic study, programmed electrical stimulation during amiodarone treatment induced VT, and
890
Heger,
Table
111.Amiodarone-associated
Patient
NS,
Prystowsky,
Pretreatment arrhythmia
and Zipes
American
exacerbation Amiodarone treatment (wk)
1 2 3
VT-S VF VT-S
4 2 2
4 5 6
VT-NS VT-S VT-S
2 2 2
7 8 9
VT-S VT-NS VT-S
2 1 1
of ventricular
October, 1983 Heart Journal
arrhythmia
Arrhythmia
Polymorphic VT; syncope Incessant VT-NS Incessant VT-S; multiple DC shocks VF VF Continuous VT; temporary pacer VF Incessant VT-S Incessant VT-S
Successful
treatment
Follow-up (mo)
Mexiletine Propranolol Quinidine
6 14 14
Mexiletine Mexiletine Tocainide
19 33 18
Mexiletine Propranolol Tocainide + propranolol
39 8 40
Nonsustained; S, sustained.
amiodarone treatment was continued. Of these 101 patients, 80 have continued long-term amiodarone treatment for a mean follow-up of 14.2 months with no recurrence of spontaneous VT. VT or VF recurred in the other 21 patients at a mean follow-up of 5.6 f 5.1 months. Therefore, amiodarone infrequently prevented induction of VT by premature ventricular stimulation, but long-term amiodarone treatment was successful in the majority of patients in whom VT was induced during initial amiodarone treatment. In one patient, electrophysiologic study wns performed at 2 weeks and repeated at 5 weeks after initiation of amiodarone treatment. At both studies, sustained VT was induced; however, during 20 months of follow-up, spontaneous VT has not recurred. On the basis of the response to programmed ventricular stimulation, antiarrhythmic drugs were added to amiodarone in 11 patients. At repeat electrophysiologic studies, VT was still induced in all 11 patients. Each of these patients continued the drug combination during follow-up, and in five of 11 patients, spontaneous VT recurred during followUP. Amioderone-rqlated arrhythmias. Amiodarone treatment appeared to exacerbate ventricular arrhythmia in nine patients (Table III). Patient 5, who was taking digoxin, was the only patient who was receiving other cardioactive drugs. In patients 2,8, and 9, multiple other antiarrhythmic drugs were associated with exacerbation of arrhythmia. In all nine patients, the amiodarone-associated arrhythmias resolved within 2 to 3 days after discontinuation of amiodarone. Patient 1 had recurrent syncope from polymorphic VT associated with a prolonged QT interval. This patient had a permanent ventricular
demand pacemaker, and recurrent polymorphic VT was prevented by increasing the rate of the permanent ventricular pacemaker. Patient 3 required multiple electrical cardioversions over 36 hours prior to resolution of the arrhythmias, and patient 6 had continuous episodes of VT that were terminated with programmed electrical stimulation using a temporary ventricular pacing electrode. The three other patients each had a single episode of VF. Permanent pacemakers were implanted in four patients who had bradyarrhythmias during amiodarone treatment. In one patient, sinus bradycardia and sinus pauses appeared to initiate episodes of VT, two patients had worsening of congestive heart failure as a result of sinus bradycardia, and one patient had dizziness and lightheadedness during bradycardia periods. In all patients, symptoms attributable to bradycardia resolved after pacemaker implantation. Pulmonary toxicity. Amiodarone treatment resulted in pulmonary toxicity in seven patients, as evidenced by diffuse pulmonary interstitial inflltrates confirmed by histologic findings consistent with fibrosing alveolitis in six patients and strongly positive results of gallium radionuclide lung scan in the other patient. These seven patients had received amiodarone for a period ranging from 2 weeks to 30 months prior to the recognition of pulmonary abnormalities. Pulmonary abnormalities were discovered at postmortem examination in one patient who died from congestive heart failure, and in one patient pulmonary abnormalities were noted 2 weeks after amiodarone was discontinued because of recurrent VT. After amiodarone was discontinued, one patient died from progressive pulmonary insu@iciency and heart failure and one patient died secondary to heart failure and sepsis. Three patients were given gluco-
Volume Number
106 4, Part 2
corticoids, one patient received no immunosuppressive treatment, and all four have had improvement of symptoms and of roentgenographic findings. Other side effects. Cornea1 microdeposits have been detected in virtually all patients receiving long-term therapy. No patient has developed abnormal visual acuity or retinal changes as a result of amiodarone. Abnormal hepatic enzymes were found commonly, but were not associated with other signs of hepatic dysfunction and did not require discontinuation of therapy, because the levels frequently returned to normal despite continued treatment with amiodarone. Blue skin discoloration, primarily in sun-exposed areas, has occurred in 19 patients receiving long-term amiodarone treatment, all for longer than 20 months. Adverse effects of nausea, anorexia, tremor, ataxia, weakness, headache, visual halos, impotence, insomnia, and constipation appeared to be dosage related. These adverse effects, noted in 76 patients, resolved after dosage reduction in 61 patients, continued despite dosage reduction in 10, and promoted discontinuation of amiodarone in five. In one patient amiodarone was discontinued because of urinary retention thought secondary to bladder atony. One patient developed symptomatic hyperthyroidism during amiodarone treatment, which spontaneously resolved after the drug was discontinued. One other patient developed symptomatic hypothyroidism that was successfully treated with thyroid replacement while amiodarone was continued. DISCUSSION
Consistent with other reports of clinical efficacy of amiodarone, results of our study indicate that at a mean follow-up of 16.2 f 13.0 months, recurrent VT or VF resistant to other antiarrhythmic drugs continued to be treated effectively with amiodarone in 64% of patients. We reported earlier, in a smaller series of patients, an overall efficacy rate of 67% during a shorter follow-up? Antiarrhythmic drugs were added to amiodarone in 32% of patients who continued long-term treatment. Adverse interactions between other antiarrhythmic agents and amiodarone have been reported12; however, we detected no exacerbation of ventricular arrhythmia during use of ant&rhythmic combinations. Our usual practice was to reduce the daily dosage of amiodarone by 50% at the time another antiarrhythmic drug was added, as well as to reduce the dose of the added drug, but it is uncertain whether this prevented adverse drug interactions. As an extension of our prior observations, this
Amiodarone
in recurrent
VT-VF
891
study indicates that amiodarone is often an effective long-term ant&rhythmic agent even when it does not prevent induction of VT by programmed electrical stimulation. It is possible that the maximum antiarrhythmic effects of amiodarone were not evident when electrophysiologic studies were performed 2 to 4 weeks after starting treatment. However, other studies in which programmed electrical stimulation was performed at longer intervals after initiation of amiodarone treatment have also confirmed the observation that VT induction during electrophysiologic study does not preclude a favorable long-term course.10,‘3~l4 In one patient, we observed that electrophysiologic parameters and characteristics of induced VT did not change between electrophysiologic studies performed 2 weeks and 5 weeks after initiation of amiodarone treatment. The question as to optimal timing for electrophysiologic evaluation during amiodarone treatment remains unanswered. It is conceivable that a favorable long-term course despite induction of VT may have been related to the use of combination antiarrhythmic drugs in some patients. However, in the 11 patients in whom antiarrhythmic drugs were added to amiodarone based solely on the response at electrophysiologic study, combination therapy did not prevent induction of VT, and during follow-up, five of these 11 patients had a recurrence of ventricular tachycardia. Therefore, patients who required combination antiarrhythmic therapy may have had arrhythmias that were more difficult to ‘manage, both during short-term treatment and long-term follow-up. Electrophysiologic parameters other than the ability to induce VT may predict long-term success of amiodarone treatment. By using discriminant function analysis, parameters that predicted longterm success of amiodarone treatment, despite induction of VT at electrophysiologic study, were the change in repetitive ventricular response status, in the mode of induction of VT, and in right ventricular effective refractory period-l5 Further application in a prospective fashion of this discriminant function equation is in progress. Amiodarone-associated arrhythmias were identified in nine (4.6%) of 196 patients given amiodarone, and have been reported by others.16-21 This frequency is not surprising, and in fact is lower than reported with many other antiarrhythmic drugsz2 In three of the nine patients, multiple other antiarrhythmic drugs produced exacerbations of arrhythmia. The mechanism of this effect of amiodarone is speculative. In one patient, there was clear evidence of QT interval prolongation and polymorphic VT
October,
892
Heger, Prystowsky,
and Zipes
that resembled torsade de pointes. Of note, in eight of the nine patients, effective long-term antiarrhythmic treatment was obtained with mexiletine, tocainide, or propranolol, agents that appear to affect cardiac electrophysiology and refractoriness differently than amiodarone. Pulmonary toxicity manifested clinically by dyspnea, hypoxemia, and diffuse pulmonary interstitial infiltrates with histologic findings of fibrosing alveolitis were noted in seven (3.6 % ) of 196 patients. Pulmonary toxicity is now a well-recognized adverse effect of amiodarone treatment.gs lo, 23-25The mechanism remains an enigma because immunologic studies have been inconclusive. However, most patients appear to improve after discontinuation of amiodarone and institution of immunosuppressive treatment. Cornea1 microdeposits are ubiquitous in patients who receive long-term treatment. Blue skin discoloration of sun-exposed areas have occurred relatively frequently in patients receiving amiodarone for longer than 20 months. This is cosmetically disfiguring, but in general has not limited long-term treatment. Other adverse effects, which most commonly include nausea, anorexia, tremor, and ataxia, have usually been dosage related and resolved after dosage decrease, but discontinuation of amiodarone treatment was necessary in eight patients. Based on these results, we conclude that amiodarone is highly effective in preventing recurrent VT and VF resistant to other antiarrhythmic drugs. The induction of VT by programmed electrical stimulation does not preclude antiarrhythmic success during long-term follow-up. The potential of amiodarone to exacerbate ventricular arrhythmia and to cause pulmonary toxicity and other adverse effects warrants careful surveillance during treatment. We thank Georgia Ladd, Linda Richmond, and Gwendolyn Berry for their invaluable assistance in patient care, data collection, and manuscript preparation, respectively. REFERENCES
1. Rosenbaum MB, Chiale PA, Ryba D, Elizari MY Control of tachyarrhythmias associated with Wolff-Parkinson-White syndrome by amiodarone hydrochloride. Am J Cardiol 34:215, 1974. 2. Rosenbaum MB, Chiale PA, Halpern MS: Clinical efficacy of amiodarone as an antiarrhythmic agent. Am J Cardiol 38:934, 1976. 3. Leak D, Eydt JN: Control of refractory cardiac arrhythmias with amiodarone. Arch Intern Med 139:425, 1979. 4. Wheeler PJ, Puritz R, Ingram DV, Chamberlain DA: Amiodarone in the treatment of refractory supraventricular and ventricular arrhythmias. Postgrad Med J 55:1, 1979. 5. Ward DE, Camm AJ, Spurrell RAJ: Clinical antiarrhythmic effects of amiodarone in patients with resistant paroxysmal tachycardias. Br Heart J 44:91, 1980.
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6. Kaski JC, Girotti LA, Messuti H, Rutitsky B, Rosenbaum MB: Long-term management of sustained, recurrent, symptomatic ventricular tachycardia with amiodarone. Circulation 84:273, 1981. 7. Podrid PJ, Lown B: Amiodarone therapy in symptomatic, sustained refractory atria1 and ventricular tachyarrhythmias. AM HEART J 101:374, 1981. 8. Nademanee K, Hendrickson JA, Cannon DS, Goldreyer BN, Singh BN: Control of refractory life-threatening ventricular tachyarrhythmias by amiodarone. AM HEART J 101:759, 1981. 9. Heger JJ, Prystowsky EN, Jackman WM, Naccarelli GV, Warfel KA, Rinkenberger RL, Zipes DP: Amiodarone: Clinical efficacy and electrophysiology during long-term therapy for recurrent ventricular tachycardia or ventricular fibrillation. N Ens1 J Med 305:539. 1981. 10. Waxman HL, Groh WC, Marchlinski FE, Buxton AE, Sadowski LM, Horowitz LN, Josephson ME, Kastor JA: Amiodarone for control of sustained ventricular tachyarrhythmia: Clinical and electrophysiologic effects in 51 patients. Am J Cardiol 50:1066, 1982. 11. Naccarelli GV, Prystowsky EN, Jackman WM, Heger JJ, Rahilly GT, Zipes DP: Role of electrophysiologic testing in managing patients who have ventricular tachycardia unrelated to coronary artery disease. Am J Cardiol 50:165, 1982. 12. Tartini R, Kappenberger L, Steinbrunn W, Meyer UA: Dangerous interaction between amiodarone and quinidine. Lancet 1:1327, 1982. 13. Finerman WB, Hamer A, Peter T, Weiss D, Mandel WJ: Electrophysiologic effects of chronic amiodarone therapy in patients with ventricular arrhythmias. AM HEART J 104:987, 1982. 14. Nademanee K, Hendrickson J, Kannan R, Singh BN: Antiarrhythmic efficacy and electrophysiologic actions of amiodarone in patients with life-threatening ventricular arrhythmias: Potent suppression of spontaneous occurring tachyarrhythmias versus inconsistent abolition of induced ventricular tachycardia. AM HEART J 103:950, 1982. 15. Naccarelli GV, Fineberg N, Zipes DP, Heger JJ, Duncan G, Prystowsky EN: Amiodarone: Discriminant analysis successfully predicts clinical outcome in patients who have ventricular tachycardia induced by programmed stimulation. Circulation 66:(suppl 2):223, 1982. 16. Veglia L, Scandiffio T, Guervicchio G: “Torsade de pointes” and amiodarone. G Ital Cardiol 8:1025, 1978. 17. McComb JM, Logan KR, Khaw MM, Geddes JS, Adgey AA: Amiodarone-induced ventricular fibrillation. Eur J Cardiol 11:381, 1980. 18. Keren A, Tzivoni D, Gottlieb S, Benhorin J, Stern S: Atypical ventricular tachycardia (torsade de pointes) induced by amiodarone: Arrhythmia previously induced by quinidine and disopyramide. Chest 81:384, 1982. 19. Westveer DC, Gadowski GA, Gordon S, Timmis GC: Amiodarone-induced ventricular tachycardia. Ann Intern Med 97:561, 1982. 20. Sclarovsky S, Lewin RF, Kracoff 0, Strasberg B, Arditta A, Agmon J: Amiodarone-induced polymorphous ventricular tachycardia. AM HEART J 1056, 1983. 21. Cui G, Huang W, Urthaler F: Ventricular flutter during treatment with amiodarone. Am J Cardiol 51:609, 1983. 22. Velebit V, Podrid P, Lown B, Cohn BH, Graboys TB: Aggravation and provocation of ventricular arrhythmias by antiarrhythmic drugs. Circulation 65:886, 1982. 23. Rotmensch HH, Liron M, Tupilski M, Laniado S: Possible association of pneumonitis with amiodarone therapy. AM HEART J 100:412, 1980. 24. Marchlinski FE, Gansler TS, Waxman HL, Josephson ME: Amiodarone pulmonary toxicity. Ann Intern Med 97:839, 1982. 25. Sobol SM, Rakita L: Pneumonitis and pulmonary fibrosis
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associated with amiodarone treatment: A possible complication of a new antiarrhythmic drug. Circulation 65819, 1982. DISCUSSION
Dr. Mandel: We all are concerned about problems that may arise during the first 3 months of amiodarone therapy. Even though we use a rather high loading dose for 7 to 10 days, it has been our practice to use a class I agent or some other standard antiarrhythmic agent in addition to amiodarone for the first 6 weeks. This dosage is then tapered after 6 to 8 weeks. We have used this approach in some significant problems during the first 4 to 12 weeks of therapy (recurrence of the patient’s arrhythmia and occasionally, death). Dr. Zipes: Such an approach may be reasonable, but we have not followed it routinely. It would be useful to see comparisons in patients given a combination of drugs and patients given amiodarone alone. We do add a drug such as lidocaine during the acute treatment phase if the patient is having recurrent VT, until amiodarone has had a chance to work. Dr. Mandel: Early in our experience, we had a number of fatalities during the first 3 months of therapy in patients given amiodarone alone. Our loading dose was lower, but we were treating nonsustained arrhythmias (e.g., frequent premature ventricular complexes and short episodes of VT). Dr. Plumb: Have you had any success using higher doses in patients who had recurrences during maintenance therapy? Dr. Zipes: Yes, in several patients our approach was to increase the dose of amiodarone. In virtually all of our patients, we try to reduce the dose to the lowest effective one. If a patient has a recurrence, we increase the dose. Or we increase the dose during the first loading period while the patient is hospitalized. Four or 5 years ago, we gave one patient amiodarone 1800 mglday and a second 2000 mglday, for 3 to 4 months, because of recurrences of ventricular arrhythmia. With those dosages, the patients could not walk or climb stairs or stand from a crouch position, and had severe nausea, vomiting, and abdominal cramps. We have not since used such high doses for long periods. That amount of amiodarone is reasonable for short loading periods, but given over several months is not tolerated. Dr. Rosenbaum: I agree. Dr. Horowitz: Have any of your patients developed more severe arrhythmias during electrophysiologic testing after amiodarone? Dr. Zipes: Only on occasion. In one of the very first patients in whom we studied amiodarone, nonsustained ventricular tachycardia was induced with premature ventricular stimulation. After we gave him amiodarone, we precipitated ventricular fibrillation with premature ventricular stimulation during sinus rhythm. We then added quinidine. Merely introducing the catheter into the right ventricle precipitated ventricular fibrillation.
Amiodarone
in recurrent
VT-VF
893
Dr. Prystowsky: In our experience using 1 and 2 premature ventricular stimuli, either the arrhythmia stayed the same or changed from sustained VT to nonsustained. It is uncommon for nonsustained VT to become sustained. Dr. Wyndham: We have had good responses by adding propranolol to amiodarone. In the laboratory, we have given propranolol intravenously. We found that we could not induce tachycardia when patients were receiving the combination. We discharged these patients while they were receiving propranolol, and gave maintenance doses for a few weeks. When they were weaned from proprano101, tachycardia remained controlled. Dr. Zipes: In a number of patients unresponsive to amiodarone, we have found it beneficial to add drugs with different electrophysiologic effects (e.g., mexiletine, tocainide, or propranolol), although these drugs alone are generally not effective in the treatment of resistant ventricular arrhythmias. Dr. Cain: Have you applied your discriminant analysis prospectively using the response to programmed stimulation? Dr. Zipes: We are doing a prospective study now, and we hope to test our analysis on patient data from other cooperating laboratories. Dr. DiMarco: We have been routinely giving our patients with VT and in danger of sudden death a combination of amiodarone and a drug that is partially effective. We generally continue the other drug unless it causes a side effect. How many of your 196 patients were receiving a second drug? Dr. Zipes: We often attempt similar combinations. Thirty-two of these patients were given an additional antiarrhythmic agent. Dr. Singh: Our experience with electrophysiologic testing is very similar to yours. We find that results of Holter recording depend on when the testing is done. There is a progressively better response, in terms of suppression of complex ectopy, with increased duration of therapy. If you use data after 3 or 4 months of therapy, there is a good correlation between the results of Holter monitoring and the clinical course. We do not use combination therapy of class 1 antiarrhythmic drugs and amiodarone. In our series of 96 patients, our data show that if amiodarone is started at high doses (1200 to 1800 mg for 1 to 2 weeks), then decreased to an intermediate level (800 to 1000 mg for 1 to 2 months), and then decreased to the lowest dose that patients can tolerate, the rate of death in the first few months is very low indeed. Because of the drug’s pharmacokinetics, it is very difficult to predict the dose based on the half-life. Dr. Zipes: We did not experience worsening ventricular arrhythmia with drug combinations when we reduced the doses of both drugs. Clearly, worsening with combinations has been reported. But in our experience, it does not occur, or occurs rarely, if the doses of both amiodarone and the class I drug are lowered. Dr. Rosenbaum: There is a place for combinations of
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Heger, Prystowsky,
and Zipes
amiodarone and other drugs. We try, however, to avoid combination therapy. When we use amiodarone alone, our results are quite similar to those reported by you and by Dr. Singh. In our experience, the combination of a beta blocker and amiodarone can be very dangerous because it can depress the sinus rate in older persons. Depression of sinus node activity is additive because it is produced by different mechanisms of the two drugs. Some older patients given a combination developed severe bradycardia and hypotension. Also, I do not recommend adding drugs that are strongly vagolytic (e.g., quinidine or disopyramide). Dr. Zipes: We have used both quinidine and disopyramide safely with amiodarone. Dr. Akhtar: Did the patients whose condition worsened with amiodarone have any other evidence of amiodarone effect besides prolongation of the QT invertal, which you described in two patients? Dr. Zipes: No. Dr. Narula: The effect of amiodarone on the conduction system may not be obvious unless there is autonomic blockade. We have studied patients with autonomic blockade and find that the sinus node is depressed even more than is obvious without autonomic blockade. I agree that amiodarone prolongs the HV interval; we have seen a prolongation of about 8 msec. We see facilitation of longitudinal dissociation within the His bundle, which is puzzling. It suggests, perhaps, that amiodarone may facilitate reentrant circuits or bundle branch reentry. Dr. Wyndham: In our experience, in one of five
American
October, 1083 Heart Journal
patients given propranolol orally, it had to be discontinued because of congestive heart failure. The other four patients continued to take propranolol and amiodarone without side effects. These patients already had permanent pacemakers, however. I agree with your conclusions about the combined effects of propranolol and amiodarone on node function, and that without a pacemaker as a backup, they can be dangerous. Dr. Sob& Did any of your patients need pacemakers, and if so, when? Dr. Zipes: Four have had pacemaker implantation because of symptomatic sinus bradycardia, generally after weeks to months of treatment. Dr. Horowitz: I agree that arrhythmia in some patients worsens with amiodarone, and we have observed one death. The small number of patients (perhaps 1% to 2 % ) in whom arrhythmia is worse in terms of morphology, rate, or clinical impact might do better with the addition of another agent or without amiodarone entirely. Dr. Zipes: In summary, we administered amiodarone therapy to a large group of patients with symptomatic recurrent ventricular tachycardia (both sustained and nonsustained) and ventricular fibrillation, in whom a large number of antiarrhythmic agents had previously been tried without success. During a follow-up of about 11/2 years, we had a success rate of about 60%. Furthermore, our data suggest that some electrophysiologic information may be helpful in predicting which patients will benefit from amiodarone therapy.
James J. Heger, M.D., Eric N. Prystowsky, Indianapolis,
M.D., and Douglas P. Zipes, M.D.
Ind.
Amiodarone, approved for general clinical use in Europe and the United Kingdom and an investigational agent in the United States since 1977, has been demonstrated to be an effective antiarrhythmic agent for treating recurrent supraventricular and ventricular tachyarrhythmias.l-lo In our initial series of 45 patients, we reported that amiodarone was effective in preventing recurrent ventricular tachycardia (VT) and ventricular fibrillation (VF) in 67% of patients? Treatment was often successful despite the continued ability to induce VT at elec-
From the Krannert Indiana University Medical Center.
Institute of Cardiology, School of Medicine, and
Supported in part by the Herman C. Indiana; grants HL-06308 and HL-07182 and Blood Institute, National Institutes of Indiana Public Health Trust; Roudebush cal Center, Indianapolis; and a Grant-In-Aid Association, Indiana Affiliate, Inc.
Department the Veterans
of Medicine, Administration
Krannert Fund, Indianapolis, from the National Heart, Lung Health; the Attorney General of Veterans Administration Medifrom the American Heart
Reprint requests: James J. Heger, M.D., Krannert 1001 W. 10th St., Indianapolis, IN 46202.
Institute
of Cardiology,
trophysiologic study during amiodarone treatment. Adverse effects were common but usually did not limit treatment, although some patients had significant and life-threatening adverse effects. This report updates our experience with amiodarone in the long-term management of recurrent VT and VF. METHODS Patient population. The study population included 196 patients who began amiodarone treatment for recurrent VT or VF and who had at least 1 month of follow-up prior to December 31, 1982. Of these 196 patients, there were 154 men and 42 women aged 18 to 77 years (mean 56.2 + 11.7 years) at the time of entry to study. Ischemic heart diseasewaspresent in 129 patients, documented by coronary arteriography in 106 patients and by clinical history and electrocardiographic evidence of prior myocardial infarction in 23 patients. Thirty-five patients had idiopathic, dilated cardiomyopathy, defined as global left ventricular dysfunction in the presenceof normal coronary arteries. Two patients had hypertrophic, nonobstructive cardiomyopathy, and one patient had an isolated right ventricular cardiomyopathy consistent with right 887
888
Heger, Prystowsky,
and Zipes
ventricular dysplasia. In three patients, cardiomyopathy was secondary to chronic systemic hypertension. Mitral valve prolapse was present in eight patients, and eight patients had other forms of valvular heart disease, including prosthetic mitral valve replacement in two, prosthetic aortic valve replacement in three, rheumatic mitral regurgitation in two, and combined mitral stenosis and regurgitation in one patient. Nine patients had no evidence of structural heart disease by cardiac catheterization, echocardiogram, or clinical examination and were classified as having primary electrical disease. One other patient had a secundum atria1 septal defect. The majority of patients had evidence of significant left ventricular dysfunction. Based on New York Heart Association criteria, 25 patients had functional class I disease, 112 functional class II, 54 functional class III, and five functional class IV, according to symptoms and signs of congestive heart failure. Arrhythmia history. Episodes of recurrent VT or VF had beenpresent from 1 to 156months (mean 15.2 + 21.5 months) before the beginning of amiodarone treatment. VT was defined as three or more consecutive premature ventricular complexes. Recurrent, sustained VT, defined as VT that produced syncope, required electrical cardioversion, or lasted longer than 30 seconds,waspresent in 95 patients. In 44 patients, recurrent VT was nonsustained. Fifty-seven patients had experienced one or episodesof cardiac arrest from VF, which required cardiopulmonary resuscitation. Each patient received from two to 10 (mean 4.4 + 1.9) drug trials prior to amiodarone treatment. Of 863 prior drug trials, 798 failed becauseof recurrence of VT or VF, and 105 patients required cardioversion or defibrillation during prior drug trials. Treatment protocol. All patients were hospitalized for at least the first 2 weeks of amiodarone treatment. At admission, all antiarrhythmic drugs were discontinued, and during hospitalization, cardiac rhythm wasmonitored continuously. Amiodarone was administered at a dosageof 800 mgl day, given as400 mg every 12hours, for 4 to 8 weeks.After the first 1 to 2 months of treatment, amiodarone dosage was gradually and progressively decreased at 3-month intervals to dosagesof 200to 600 mg/day. The timing and magnitude of dosagechangeswere also influenced by the control of VT and the presenceof symptomatic adverse effects. Patients who entered the investigation during the last 6 months of the study period received an initial amiodarone dose of 1600 mg/day for the first 2 weeks of treatment. The dosagewas then reduced to 800 mg/day, and the dosage guidelines described previously for outpatient therapy were followed. Antiarrhythmic efficacy of amiodarone during initial dosingwasassessed only after at least 7 days of treatment. If recurrent VF or sustained VT recurred and produced sudden cardiovascular collapseafter 7 days of treatment, amiodarone wasdiscontinued. If during the initial month of treatment there continued to be episodesof nonsus-
American
October, 1983 Heart Journal
tained or sustainedVT that were hemodynamically stable, amiodarone was continued at a higher dosage,up to 800 mglday, or a secondantiarrhythmic drug wasadded. The specific choice of a secondantiarrhythmic drug wasbased, when possible,on the individual patient’s responseto that drug during prior trials. In two patients who had recurrent VT during the first months of treatment, amiodarone dosage was progressively increased to 1800 and 2000 mg/day, for 2 and 4 months, respectively. Prior to amiodarone treatment a drug-free, control electrophysiologic study was performed in 115 patients according to a previously described protocol for programmed electrical stimulation of the heart.” In 101 of 115 patients in whom VT was induced at control study, and in another 17 patients who did not undergo a control study, electrophysiologicstudieswere performed after 2 or more weeksof amiodarone treatment. The results of the electrophysiologic study only influenced the decision to continue amiodarone or to add additional antiarrhythmic drugs if the VT induced during programmed electrical stimulation had a cycle length <350 msec.In 11 patients, antiarrhythmic drugs were added to amiodarone, based solely on the responseof VT induction during electrophysiologic study. The electrophysiologic study was then repeated in these patients while they received the drug combination. RESULTS Clinical
antiarrhythmic
efficacy.
During a mean fol-
(range 1 to 57 months), 126 (64%) of 196 patients continued to receive amiodarone treatment. These 126 patients included 35 (61% ) of 57 who had recurrent ventricular fibrillation, 59 (62%) of 95 who had recurrent, sustained ventricular tachycardia, and 32 (73 % ) of 44 who had recurrent, nonsustained VT. low-up
of 16.2 -t 13.0 months
The results after the initial month of amiodarone
treatment are outlined in Table I. Amiodarone treatment was discontinued because of recurrent, spontaneous VT or VF in 14 patients, VT induced during electrophysiologic study in two patients, adverse effects in two patients, and death from heart failure in one. Of the 73 patients who had recurrence of spontaneous VT or VF, amiodarone alone (eight patients) or with an additional antiarrhythmic drug (51 patients) was continued in 59 patients, and 35 of these were given amiodarone throughout the follow-
up period. The outcome of long-term amiodarone treatment in 177 patients is outlined in Table II. No recurrence of spontaneous VT or VF was evident in 139 patients, of whom 112 have continued long-term treatment. VT or VF recurred in 38 patients. Fifteen patients had sudden cardiac death after 1 to 43 months (mean 10.4 F 10.6 months) of treatment. Of
six patients
in whom amiodarone
was discontinued
Volume Number
Table
106 4, Part 2
Amiodarone
1 (n = 107) 2 (n = 73)
3 (n = 13)
Table
(n = 3)
Response No spontaneous VT or VF Recurrent spontaneous VT
Treatment or VF
Treatment change because VT induced electrophysiologic study Adverse side effects Death from congestive heart failure
089
at
Amiodarone Amiodarone Antiarrhythmic Amiodarone Antiarrhythmic Amiodarone Amiodarone Amiodarone
Number
continued continued alone added discontinued added discontinued discontinued discontinued
of
patients
107 8 51 14 11 2 2 1
II. Outcome of long-term treatment with amiodarone Group
Response
1 (n = 139)
No spontaneous VT or VF Adverse side effects Death from CHF Noncardiac death Recurrent VT or VF
2 (n = 38)
Sudden *Three
VT- VF
I. Outcome of initial treatment with amiodarone for 1 month in 196 patients Group
4
in recurrent
of these patients
cardiac
died from congestive
death
Treatment Amiodarone Amiondarone
continued discontinued
Amiodarone Amiodarone
continued discontinued
Number
of
patients
112 10 16 1 17’ 6 15
heart failure.
because of recurrent arrhythmia, two had cardiac arrest from polymorphic VT possibly related to amiodarone, one was resuscitated from recurrent spontaneous VF, and three had recurrence of sustained VT. Two of the latter three patients underwent left ventricular aneurysmectomy and endocardial resection, and the other four patients were given other antiarrhythmic drugs. In 17 patients, admiodarone treatment was continued despite recurrent arrhythmia during longterm follow-up. One patient, who had received a radiofrequency burst ventricular pacemaker to terminate recurrent VT, successfully used the device on four occasions during 22 months of follow-up. In one patient who had recurrent VF after 1 month of treatment, amiodarone was continued in conjunction with implantation of an automatic defibrillator. Antiarrhythmic drugs were added in five patients, and one patient received an atria1 demand pacemaker because recurrent VT occurred during periods of spontaneous sinus bradycardia. In the other nine patients, the dosage of amiodarone was temporarily increased in six patients and remained unchanged in three during long-term follow-up. During continued follow-up of these 17 patients, three patients died from congestive heart failure that antedated onset of admiodarone treatment, and 14 patients have continued amiodarone treatment. In 41 of 126 patients receiving long-term amiodarone treatment, antiarrhythmic drugs have been added to amiodarone: aprindine in 12, aprindine and
propranolol in one, quinidine in 10, encainide in six, disopyramide in five, mexiletine in two, mexiletine and propranolol in one, propranolol alone in two, procainamide in one, and propafenone in one. In no patient did a drug combination appear to result in exacerbation of either ventricular arrhythmia or congestive heart failure. During the course of treatment, amiodarone was discontinued in 12 patients because of noncardiac adverse effects: pulmonary toxicity in five patients, nausea and anorexia in four, tremor and ataxia in one, urinary retention in one, and hyperthyroidism in one. Electrophysiologic studies. Electrophysiologic studies were performed after at least 2 weeks of amiodarone treatment in 101 patients in whom VT was induced at control study and in 17 patients who did not undergo a control study. Of the 101 patients in whom serial electrophysiologic studies were performed, amiodarone was discontinued in two patients after induction of sustained VT. In 15 patients, including two who received amiodarone combined with quinidine because of spontaneous VT, amiodarone prevented VT induction at repeat electrophysiologic study. None of these 15 patients had recurrent VT during long-term amiodarone treatment. In the other 84 serially studied patients and in 17 patients who did not undergo a control electrophysiologic study, programmed electrical stimulation during amiodarone treatment induced VT, and
890
Heger,
Table
111.Amiodarone-associated
Patient
NS,
Prystowsky,
Pretreatment arrhythmia
and Zipes
American
exacerbation Amiodarone treatment (wk)
1 2 3
VT-S VF VT-S
4 2 2
4 5 6
VT-NS VT-S VT-S
2 2 2
7 8 9
VT-S VT-NS VT-S
2 1 1
of ventricular
October, 1983 Heart Journal
arrhythmia
Arrhythmia
Polymorphic VT; syncope Incessant VT-NS Incessant VT-S; multiple DC shocks VF VF Continuous VT; temporary pacer VF Incessant VT-S Incessant VT-S
Successful
treatment
Follow-up (mo)
Mexiletine Propranolol Quinidine
6 14 14
Mexiletine Mexiletine Tocainide
19 33 18
Mexiletine Propranolol Tocainide + propranolol
39 8 40
Nonsustained; S, sustained.
amiodarone treatment was continued. Of these 101 patients, 80 have continued long-term amiodarone treatment for a mean follow-up of 14.2 months with no recurrence of spontaneous VT. VT or VF recurred in the other 21 patients at a mean follow-up of 5.6 f 5.1 months. Therefore, amiodarone infrequently prevented induction of VT by premature ventricular stimulation, but long-term amiodarone treatment was successful in the majority of patients in whom VT was induced during initial amiodarone treatment. In one patient, electrophysiologic study wns performed at 2 weeks and repeated at 5 weeks after initiation of amiodarone treatment. At both studies, sustained VT was induced; however, during 20 months of follow-up, spontaneous VT has not recurred. On the basis of the response to programmed ventricular stimulation, antiarrhythmic drugs were added to amiodarone in 11 patients. At repeat electrophysiologic studies, VT was still induced in all 11 patients. Each of these patients continued the drug combination during follow-up, and in five of 11 patients, spontaneous VT recurred during followUP. Amioderone-rqlated arrhythmias. Amiodarone treatment appeared to exacerbate ventricular arrhythmia in nine patients (Table III). Patient 5, who was taking digoxin, was the only patient who was receiving other cardioactive drugs. In patients 2,8, and 9, multiple other antiarrhythmic drugs were associated with exacerbation of arrhythmia. In all nine patients, the amiodarone-associated arrhythmias resolved within 2 to 3 days after discontinuation of amiodarone. Patient 1 had recurrent syncope from polymorphic VT associated with a prolonged QT interval. This patient had a permanent ventricular
demand pacemaker, and recurrent polymorphic VT was prevented by increasing the rate of the permanent ventricular pacemaker. Patient 3 required multiple electrical cardioversions over 36 hours prior to resolution of the arrhythmias, and patient 6 had continuous episodes of VT that were terminated with programmed electrical stimulation using a temporary ventricular pacing electrode. The three other patients each had a single episode of VF. Permanent pacemakers were implanted in four patients who had bradyarrhythmias during amiodarone treatment. In one patient, sinus bradycardia and sinus pauses appeared to initiate episodes of VT, two patients had worsening of congestive heart failure as a result of sinus bradycardia, and one patient had dizziness and lightheadedness during bradycardia periods. In all patients, symptoms attributable to bradycardia resolved after pacemaker implantation. Pulmonary toxicity. Amiodarone treatment resulted in pulmonary toxicity in seven patients, as evidenced by diffuse pulmonary interstitial inflltrates confirmed by histologic findings consistent with fibrosing alveolitis in six patients and strongly positive results of gallium radionuclide lung scan in the other patient. These seven patients had received amiodarone for a period ranging from 2 weeks to 30 months prior to the recognition of pulmonary abnormalities. Pulmonary abnormalities were discovered at postmortem examination in one patient who died from congestive heart failure, and in one patient pulmonary abnormalities were noted 2 weeks after amiodarone was discontinued because of recurrent VT. After amiodarone was discontinued, one patient died from progressive pulmonary insu@iciency and heart failure and one patient died secondary to heart failure and sepsis. Three patients were given gluco-
Volume Number
106 4, Part 2
corticoids, one patient received no immunosuppressive treatment, and all four have had improvement of symptoms and of roentgenographic findings. Other side effects. Cornea1 microdeposits have been detected in virtually all patients receiving long-term therapy. No patient has developed abnormal visual acuity or retinal changes as a result of amiodarone. Abnormal hepatic enzymes were found commonly, but were not associated with other signs of hepatic dysfunction and did not require discontinuation of therapy, because the levels frequently returned to normal despite continued treatment with amiodarone. Blue skin discoloration, primarily in sun-exposed areas, has occurred in 19 patients receiving long-term amiodarone treatment, all for longer than 20 months. Adverse effects of nausea, anorexia, tremor, ataxia, weakness, headache, visual halos, impotence, insomnia, and constipation appeared to be dosage related. These adverse effects, noted in 76 patients, resolved after dosage reduction in 61 patients, continued despite dosage reduction in 10, and promoted discontinuation of amiodarone in five. In one patient amiodarone was discontinued because of urinary retention thought secondary to bladder atony. One patient developed symptomatic hyperthyroidism during amiodarone treatment, which spontaneously resolved after the drug was discontinued. One other patient developed symptomatic hypothyroidism that was successfully treated with thyroid replacement while amiodarone was continued. DISCUSSION
Consistent with other reports of clinical efficacy of amiodarone, results of our study indicate that at a mean follow-up of 16.2 f 13.0 months, recurrent VT or VF resistant to other antiarrhythmic drugs continued to be treated effectively with amiodarone in 64% of patients. We reported earlier, in a smaller series of patients, an overall efficacy rate of 67% during a shorter follow-up? Antiarrhythmic drugs were added to amiodarone in 32% of patients who continued long-term treatment. Adverse interactions between other antiarrhythmic agents and amiodarone have been reported12; however, we detected no exacerbation of ventricular arrhythmia during use of ant&rhythmic combinations. Our usual practice was to reduce the daily dosage of amiodarone by 50% at the time another antiarrhythmic drug was added, as well as to reduce the dose of the added drug, but it is uncertain whether this prevented adverse drug interactions. As an extension of our prior observations, this
Amiodarone
in recurrent
VT-VF
891
study indicates that amiodarone is often an effective long-term ant&rhythmic agent even when it does not prevent induction of VT by programmed electrical stimulation. It is possible that the maximum antiarrhythmic effects of amiodarone were not evident when electrophysiologic studies were performed 2 to 4 weeks after starting treatment. However, other studies in which programmed electrical stimulation was performed at longer intervals after initiation of amiodarone treatment have also confirmed the observation that VT induction during electrophysiologic study does not preclude a favorable long-term course.10,‘3~l4 In one patient, we observed that electrophysiologic parameters and characteristics of induced VT did not change between electrophysiologic studies performed 2 weeks and 5 weeks after initiation of amiodarone treatment. The question as to optimal timing for electrophysiologic evaluation during amiodarone treatment remains unanswered. It is conceivable that a favorable long-term course despite induction of VT may have been related to the use of combination antiarrhythmic drugs in some patients. However, in the 11 patients in whom antiarrhythmic drugs were added to amiodarone based solely on the response at electrophysiologic study, combination therapy did not prevent induction of VT, and during follow-up, five of these 11 patients had a recurrence of ventricular tachycardia. Therefore, patients who required combination antiarrhythmic therapy may have had arrhythmias that were more difficult to ‘manage, both during short-term treatment and long-term follow-up. Electrophysiologic parameters other than the ability to induce VT may predict long-term success of amiodarone treatment. By using discriminant function analysis, parameters that predicted longterm success of amiodarone treatment, despite induction of VT at electrophysiologic study, were the change in repetitive ventricular response status, in the mode of induction of VT, and in right ventricular effective refractory period-l5 Further application in a prospective fashion of this discriminant function equation is in progress. Amiodarone-associated arrhythmias were identified in nine (4.6%) of 196 patients given amiodarone, and have been reported by others.16-21 This frequency is not surprising, and in fact is lower than reported with many other antiarrhythmic drugsz2 In three of the nine patients, multiple other antiarrhythmic drugs produced exacerbations of arrhythmia. The mechanism of this effect of amiodarone is speculative. In one patient, there was clear evidence of QT interval prolongation and polymorphic VT
October,
892
Heger, Prystowsky,
and Zipes
that resembled torsade de pointes. Of note, in eight of the nine patients, effective long-term antiarrhythmic treatment was obtained with mexiletine, tocainide, or propranolol, agents that appear to affect cardiac electrophysiology and refractoriness differently than amiodarone. Pulmonary toxicity manifested clinically by dyspnea, hypoxemia, and diffuse pulmonary interstitial infiltrates with histologic findings of fibrosing alveolitis were noted in seven (3.6 % ) of 196 patients. Pulmonary toxicity is now a well-recognized adverse effect of amiodarone treatment.gs lo, 23-25The mechanism remains an enigma because immunologic studies have been inconclusive. However, most patients appear to improve after discontinuation of amiodarone and institution of immunosuppressive treatment. Cornea1 microdeposits are ubiquitous in patients who receive long-term treatment. Blue skin discoloration of sun-exposed areas have occurred relatively frequently in patients receiving amiodarone for longer than 20 months. This is cosmetically disfiguring, but in general has not limited long-term treatment. Other adverse effects, which most commonly include nausea, anorexia, tremor, and ataxia, have usually been dosage related and resolved after dosage decrease, but discontinuation of amiodarone treatment was necessary in eight patients. Based on these results, we conclude that amiodarone is highly effective in preventing recurrent VT and VF resistant to other antiarrhythmic drugs. The induction of VT by programmed electrical stimulation does not preclude antiarrhythmic success during long-term follow-up. The potential of amiodarone to exacerbate ventricular arrhythmia and to cause pulmonary toxicity and other adverse effects warrants careful surveillance during treatment. We thank Georgia Ladd, Linda Richmond, and Gwendolyn Berry for their invaluable assistance in patient care, data collection, and manuscript preparation, respectively. REFERENCES
1. Rosenbaum MB, Chiale PA, Ryba D, Elizari MY Control of tachyarrhythmias associated with Wolff-Parkinson-White syndrome by amiodarone hydrochloride. Am J Cardiol 34:215, 1974. 2. Rosenbaum MB, Chiale PA, Halpern MS: Clinical efficacy of amiodarone as an antiarrhythmic agent. Am J Cardiol 38:934, 1976. 3. Leak D, Eydt JN: Control of refractory cardiac arrhythmias with amiodarone. Arch Intern Med 139:425, 1979. 4. Wheeler PJ, Puritz R, Ingram DV, Chamberlain DA: Amiodarone in the treatment of refractory supraventricular and ventricular arrhythmias. Postgrad Med J 55:1, 1979. 5. Ward DE, Camm AJ, Spurrell RAJ: Clinical antiarrhythmic effects of amiodarone in patients with resistant paroxysmal tachycardias. Br Heart J 44:91, 1980.
American
Heart
1983 Journal
6. Kaski JC, Girotti LA, Messuti H, Rutitsky B, Rosenbaum MB: Long-term management of sustained, recurrent, symptomatic ventricular tachycardia with amiodarone. Circulation 84:273, 1981. 7. Podrid PJ, Lown B: Amiodarone therapy in symptomatic, sustained refractory atria1 and ventricular tachyarrhythmias. AM HEART J 101:374, 1981. 8. Nademanee K, Hendrickson JA, Cannon DS, Goldreyer BN, Singh BN: Control of refractory life-threatening ventricular tachyarrhythmias by amiodarone. AM HEART J 101:759, 1981. 9. Heger JJ, Prystowsky EN, Jackman WM, Naccarelli GV, Warfel KA, Rinkenberger RL, Zipes DP: Amiodarone: Clinical efficacy and electrophysiology during long-term therapy for recurrent ventricular tachycardia or ventricular fibrillation. N Ens1 J Med 305:539. 1981. 10. Waxman HL, Groh WC, Marchlinski FE, Buxton AE, Sadowski LM, Horowitz LN, Josephson ME, Kastor JA: Amiodarone for control of sustained ventricular tachyarrhythmia: Clinical and electrophysiologic effects in 51 patients. Am J Cardiol 50:1066, 1982. 11. Naccarelli GV, Prystowsky EN, Jackman WM, Heger JJ, Rahilly GT, Zipes DP: Role of electrophysiologic testing in managing patients who have ventricular tachycardia unrelated to coronary artery disease. Am J Cardiol 50:165, 1982. 12. Tartini R, Kappenberger L, Steinbrunn W, Meyer UA: Dangerous interaction between amiodarone and quinidine. Lancet 1:1327, 1982. 13. Finerman WB, Hamer A, Peter T, Weiss D, Mandel WJ: Electrophysiologic effects of chronic amiodarone therapy in patients with ventricular arrhythmias. AM HEART J 104:987, 1982. 14. Nademanee K, Hendrickson J, Kannan R, Singh BN: Antiarrhythmic efficacy and electrophysiologic actions of amiodarone in patients with life-threatening ventricular arrhythmias: Potent suppression of spontaneous occurring tachyarrhythmias versus inconsistent abolition of induced ventricular tachycardia. AM HEART J 103:950, 1982. 15. Naccarelli GV, Fineberg N, Zipes DP, Heger JJ, Duncan G, Prystowsky EN: Amiodarone: Discriminant analysis successfully predicts clinical outcome in patients who have ventricular tachycardia induced by programmed stimulation. Circulation 66:(suppl 2):223, 1982. 16. Veglia L, Scandiffio T, Guervicchio G: “Torsade de pointes” and amiodarone. G Ital Cardiol 8:1025, 1978. 17. McComb JM, Logan KR, Khaw MM, Geddes JS, Adgey AA: Amiodarone-induced ventricular fibrillation. Eur J Cardiol 11:381, 1980. 18. Keren A, Tzivoni D, Gottlieb S, Benhorin J, Stern S: Atypical ventricular tachycardia (torsade de pointes) induced by amiodarone: Arrhythmia previously induced by quinidine and disopyramide. Chest 81:384, 1982. 19. Westveer DC, Gadowski GA, Gordon S, Timmis GC: Amiodarone-induced ventricular tachycardia. Ann Intern Med 97:561, 1982. 20. Sclarovsky S, Lewin RF, Kracoff 0, Strasberg B, Arditta A, Agmon J: Amiodarone-induced polymorphous ventricular tachycardia. AM HEART J 1056, 1983. 21. Cui G, Huang W, Urthaler F: Ventricular flutter during treatment with amiodarone. Am J Cardiol 51:609, 1983. 22. Velebit V, Podrid P, Lown B, Cohn BH, Graboys TB: Aggravation and provocation of ventricular arrhythmias by antiarrhythmic drugs. Circulation 65:886, 1982. 23. Rotmensch HH, Liron M, Tupilski M, Laniado S: Possible association of pneumonitis with amiodarone therapy. AM HEART J 100:412, 1980. 24. Marchlinski FE, Gansler TS, Waxman HL, Josephson ME: Amiodarone pulmonary toxicity. Ann Intern Med 97:839, 1982. 25. Sobol SM, Rakita L: Pneumonitis and pulmonary fibrosis
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associated with amiodarone treatment: A possible complication of a new antiarrhythmic drug. Circulation 65819, 1982. DISCUSSION
Dr. Mandel: We all are concerned about problems that may arise during the first 3 months of amiodarone therapy. Even though we use a rather high loading dose for 7 to 10 days, it has been our practice to use a class I agent or some other standard antiarrhythmic agent in addition to amiodarone for the first 6 weeks. This dosage is then tapered after 6 to 8 weeks. We have used this approach in some significant problems during the first 4 to 12 weeks of therapy (recurrence of the patient’s arrhythmia and occasionally, death). Dr. Zipes: Such an approach may be reasonable, but we have not followed it routinely. It would be useful to see comparisons in patients given a combination of drugs and patients given amiodarone alone. We do add a drug such as lidocaine during the acute treatment phase if the patient is having recurrent VT, until amiodarone has had a chance to work. Dr. Mandel: Early in our experience, we had a number of fatalities during the first 3 months of therapy in patients given amiodarone alone. Our loading dose was lower, but we were treating nonsustained arrhythmias (e.g., frequent premature ventricular complexes and short episodes of VT). Dr. Plumb: Have you had any success using higher doses in patients who had recurrences during maintenance therapy? Dr. Zipes: Yes, in several patients our approach was to increase the dose of amiodarone. In virtually all of our patients, we try to reduce the dose to the lowest effective one. If a patient has a recurrence, we increase the dose. Or we increase the dose during the first loading period while the patient is hospitalized. Four or 5 years ago, we gave one patient amiodarone 1800 mglday and a second 2000 mglday, for 3 to 4 months, because of recurrences of ventricular arrhythmia. With those dosages, the patients could not walk or climb stairs or stand from a crouch position, and had severe nausea, vomiting, and abdominal cramps. We have not since used such high doses for long periods. That amount of amiodarone is reasonable for short loading periods, but given over several months is not tolerated. Dr. Rosenbaum: I agree. Dr. Horowitz: Have any of your patients developed more severe arrhythmias during electrophysiologic testing after amiodarone? Dr. Zipes: Only on occasion. In one of the very first patients in whom we studied amiodarone, nonsustained ventricular tachycardia was induced with premature ventricular stimulation. After we gave him amiodarone, we precipitated ventricular fibrillation with premature ventricular stimulation during sinus rhythm. We then added quinidine. Merely introducing the catheter into the right ventricle precipitated ventricular fibrillation.
Amiodarone
in recurrent
VT-VF
893
Dr. Prystowsky: In our experience using 1 and 2 premature ventricular stimuli, either the arrhythmia stayed the same or changed from sustained VT to nonsustained. It is uncommon for nonsustained VT to become sustained. Dr. Wyndham: We have had good responses by adding propranolol to amiodarone. In the laboratory, we have given propranolol intravenously. We found that we could not induce tachycardia when patients were receiving the combination. We discharged these patients while they were receiving propranolol, and gave maintenance doses for a few weeks. When they were weaned from proprano101, tachycardia remained controlled. Dr. Zipes: In a number of patients unresponsive to amiodarone, we have found it beneficial to add drugs with different electrophysiologic effects (e.g., mexiletine, tocainide, or propranolol), although these drugs alone are generally not effective in the treatment of resistant ventricular arrhythmias. Dr. Cain: Have you applied your discriminant analysis prospectively using the response to programmed stimulation? Dr. Zipes: We are doing a prospective study now, and we hope to test our analysis on patient data from other cooperating laboratories. Dr. DiMarco: We have been routinely giving our patients with VT and in danger of sudden death a combination of amiodarone and a drug that is partially effective. We generally continue the other drug unless it causes a side effect. How many of your 196 patients were receiving a second drug? Dr. Zipes: We often attempt similar combinations. Thirty-two of these patients were given an additional antiarrhythmic agent. Dr. Singh: Our experience with electrophysiologic testing is very similar to yours. We find that results of Holter recording depend on when the testing is done. There is a progressively better response, in terms of suppression of complex ectopy, with increased duration of therapy. If you use data after 3 or 4 months of therapy, there is a good correlation between the results of Holter monitoring and the clinical course. We do not use combination therapy of class 1 antiarrhythmic drugs and amiodarone. In our series of 96 patients, our data show that if amiodarone is started at high doses (1200 to 1800 mg for 1 to 2 weeks), then decreased to an intermediate level (800 to 1000 mg for 1 to 2 months), and then decreased to the lowest dose that patients can tolerate, the rate of death in the first few months is very low indeed. Because of the drug’s pharmacokinetics, it is very difficult to predict the dose based on the half-life. Dr. Zipes: We did not experience worsening ventricular arrhythmia with drug combinations when we reduced the doses of both drugs. Clearly, worsening with combinations has been reported. But in our experience, it does not occur, or occurs rarely, if the doses of both amiodarone and the class I drug are lowered. Dr. Rosenbaum: There is a place for combinations of
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and Zipes
amiodarone and other drugs. We try, however, to avoid combination therapy. When we use amiodarone alone, our results are quite similar to those reported by you and by Dr. Singh. In our experience, the combination of a beta blocker and amiodarone can be very dangerous because it can depress the sinus rate in older persons. Depression of sinus node activity is additive because it is produced by different mechanisms of the two drugs. Some older patients given a combination developed severe bradycardia and hypotension. Also, I do not recommend adding drugs that are strongly vagolytic (e.g., quinidine or disopyramide). Dr. Zipes: We have used both quinidine and disopyramide safely with amiodarone. Dr. Akhtar: Did the patients whose condition worsened with amiodarone have any other evidence of amiodarone effect besides prolongation of the QT invertal, which you described in two patients? Dr. Zipes: No. Dr. Narula: The effect of amiodarone on the conduction system may not be obvious unless there is autonomic blockade. We have studied patients with autonomic blockade and find that the sinus node is depressed even more than is obvious without autonomic blockade. I agree that amiodarone prolongs the HV interval; we have seen a prolongation of about 8 msec. We see facilitation of longitudinal dissociation within the His bundle, which is puzzling. It suggests, perhaps, that amiodarone may facilitate reentrant circuits or bundle branch reentry. Dr. Wyndham: In our experience, in one of five
American
October, 1083 Heart Journal
patients given propranolol orally, it had to be discontinued because of congestive heart failure. The other four patients continued to take propranolol and amiodarone without side effects. These patients already had permanent pacemakers, however. I agree with your conclusions about the combined effects of propranolol and amiodarone on node function, and that without a pacemaker as a backup, they can be dangerous. Dr. Sob& Did any of your patients need pacemakers, and if so, when? Dr. Zipes: Four have had pacemaker implantation because of symptomatic sinus bradycardia, generally after weeks to months of treatment. Dr. Horowitz: I agree that arrhythmia in some patients worsens with amiodarone, and we have observed one death. The small number of patients (perhaps 1% to 2 % ) in whom arrhythmia is worse in terms of morphology, rate, or clinical impact might do better with the addition of another agent or without amiodarone entirely. Dr. Zipes: In summary, we administered amiodarone therapy to a large group of patients with symptomatic recurrent ventricular tachycardia (both sustained and nonsustained) and ventricular fibrillation, in whom a large number of antiarrhythmic agents had previously been tried without success. During a follow-up of about 11/2 years, we had a success rate of about 60%. Furthermore, our data suggest that some electrophysiologic information may be helpful in predicting which patients will benefit from amiodarone therapy.