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Prognostic value of the changes in the mode of ventricular tachycardia induction during therapy with amiodarone or amiodarone and a class 1A antiarrhythmic agent
ARRHYTHMIAS
AND CONDUCTION DISTURBANCES
Prognostic Value of the Changesin the Mode of Ventricular TachycardiaInduction During Therapy with Amiodaroneor Amiodaroneand a Class 1A Antiarrhythmic Agent SO0 G. KIM, MD, SAMUEL D. FELDER, MD, ILONA FIGURA, MD, DEBRA R. JOHNSTON, RN, ANTHONY D. MERCANDO, MD, and JOHN D. FISHER, MD
78 % and 78 % in patients with inefficacy, respectively; and 80 % and 80 % in patients with efficacy by criterion Ill and 79% and 79% in patients with inefficacy, respectively (difference not significant for all). From the results of follow-up at 2 years, sensitivities of criteria I, II and Ill were 92 % , 75% and 33%, respectively. Specificities were 17%, 26 % and 70 % , respectively, and predictive accuracies were 43 % , 43 % and 67 % , respectively. Thus, patients with efficacy by criterion I appear to have a better prognosis when compared with patients with inefficacy. However, many patients with inefficacy by criterion I had a good outcome (nonspecificity). Criteria II and Ill based on the changes in the mode of VT induction may not predict clinical outcomes. Criterion II is sensitive but nonspecific and criterion Ill is specific but insensitive.
The prognostic value of 3 previously reported programmed stimulation efficacy criteria was studied in 70 patients taking amiodarone for sustained ventricular tachycardia (VT). At baseline all patients had VT inducible by programmed stimulation. After amiodarone loading (935 f 271 mg/day for I6 f 7 days), efficacy of amiodarone was determined by 3 programmed stimulation criteria (criterion I = VT not inducible or I5 beats or less; criterion II = VT not inducible or harder to induce; criterion Ill = VT not easier to induce). Amiodarone was effective in 12, 25 and 49 of 70 patients by criteria I, II and Ill, respectively. There were I6 recurrences or cardiac arrest during the follow-up period (I 9 f I9 months). Actuarial arrhythmia-free survival rates at I and 2 years were: 90 % and 90% in patients with efficacy by criterion I and 76% and 76% in patients with inefficacy, respectively; 64% and 84% in patients with efficacy by criterion II and
(Am J Cardiol 1987;59:1314-1318)
T
he role of programmed stimulation in assessing efficacy and inefficacy of amiodarone in patients with malignant ventricular arrhythmia is controversial.“l Many investigators1-7 have reported poor predictive values of programmed stimulation in patients taking From the Department of Medicine, Division of Glrtliology, Arrhythmia Service, Montefiorc h4edical Center-Mnntcfiore Hospital/Moses Division and the Albert Einstein College of Medicine, Bronx, New York. Manrwript rcceivcd October 20. 1986; rcvisctl mwuscript rcccivetl and accepted January 12. 1987. Address for reprints: SW G. Kim, MD, Division of Cardiob g>‘. Montcfiorc Mcdiwl Center. 111 East 210th Street, Bronx. New York loG7. 1314
amiodarone. Other investigatorsa-I1 however, reported that programmed stimulation is predictive in such patients. They suggested that certain changes in the mode of ventricular tachycardia [VT) induction produced by amiodarone therapy are predictive.8,10.1’Horowitz et allo reported that suppression of inducible VT with amiodarone predicts a good outcome compared with the results of patients with persistence of inducible VT, McGovern et al8 reported that if VT is no longer inducible or harder to induce by programmed stimulation, a patient will have a good outcome with amiodarone. Naccarelli et al,” however, reported that easier induction of VT predicts a poor outcome with amiodarone therapy. It is therefore un-
June 1, 1987
known which efficacy criterion is most predictive. TO compare the predictive values of 3 reported programmed stimulation efficacy criteria, we studied 70 patients taking amiodarone for recurrent sustained VT or ventricular fibrillation (VF). Efficacy of amiodarone in each patient was determined by these 3 programmed stimulation criteria.
Methods Patients: Seventy patients (54 men, 16 women, mean age 61 f 10 years] with recurrent, sustained VT with hemodynamic compromise (66 patients) or VF (4 patients] were studied. Fifty patients had coronary artery disease and 20 had idiopathic dilated cardiomyopathy. No arrhythmia was associated with an acute myocardial infarction or remediable causes (such as hypokalemia, digitalis toxicity or drug-induced arrhythmia). Criteria for admission to the study also included sustained VT by programmed stimulation requiring intervention for termination during a baseline study in the absence of antiarrhythmic agents. Patients with arrhythmias refractory to conventional nonexperimental drugs or patients with intolerable side effects from conventional drugs were entered into this study. Programmed stimulation: Programmed stimulation protocol used in this study has been rep0rted.l” Single, double or triple premature stimuli were introduced during sinus rhythm initially, then during ventricular pacing at cycle lengths of 600 to 400 ms. When VT could not be induced at the right ventricular apex, the stimulation protocol was repeated at the right ventricular outflow. The endpoint of stimulation was (1) induction of a sustained VT that required intervention for termination or (2) completion of the stimulation protocol. The modes of induction of VT at baseline and with amiodarone therapy in each patient were compared. Because of our stimulation protocol calling for 3 extrastimuli during sinus rhythm before 1 or 2 extrastimuli during ventricular pacing, the hierarchy of ease of induction was defined as follows: sinus rhythm + 1 extrastimulus, 2 extrastimuli, 3 extrastimuli, ventricular pacing + 1 extrastimulus, 2 extrastimuli and 3 extrastimuli. Three different programmed stimulation efficacy criteria reported to be predictive8,*0,‘1 were used. Amiodarone was considered effective when VT was no longer inducible or nonsustained (15 beats or less] (criterion I),“’ VT was noninducible or harder to induce compared with the baseline (criterion II),” or VT was not easier to induce (unchanged. with same mode of induction, harder or noninducible) [criterion III).l’ Study design: All patients gave informed consent before the study for serial drug testing by programmed stimulation and administration of amiodarone. All patients had a baseline programmed stimulation study at least 5 half-lives after discontinuation of all antiarrhythmic medications. Amiodarone was given orally twice daily in equally divided doses. All patients received a loading dose of amiodarone (935 f 271 mg/ day) for 16 f 7 days followed by a maintenance dose of
TABLE
THE AMERICAN
I
Results
JOURNAL
of Programmed
VT induction by SR SR SR VP VP VP
f + + + + +
OF CARDIOLOGY
1 2 3 1 2 3
No VT Inducible
Volume 59
1315
Stimulation
Pre-RX (No. of pts)
Post-Rx (No. of pts)
0 4 12 6 19 29
2 2 11 7 18 18 12
Rx = treatment; SR + 1, 2 or 3 = sinus rhythm + 1. 2 or 3 extrastimuli; VP + 1. 2 or 3 = ventricular pacing + 1, 2 or 3 extrastimuli; VT = ventricular tachycardia.
356 f 109 mg/day. Programmed stimulation was repeated at the end of amiodarone loading. In some patients with a hemodynamically significant VT inducible by programmed stimulation with amiodarone, a class 1A conventional antiarrhythmic agent (quinidine, procainamide or disopyramide) was added (18 patients)l” and programmed stimulation was repeated before discharge from the hospital. The endpoint of follow-up was recurrence of sustained VT or sudden death (death within an hour after the onset of symptom], other death, discontinuation of the discharge regimen because of adverse effects, or arrhythmia-free survival as of February 15, 1986. Statistical methods: The mean f standard deviation was used as the index of dispersion of observed values. The Kaplan-Meier’s method was used to generate actuarial survival rates of each group. The differences among groups were tested by the log-rank test for statistical significance. A Z-tailed p value -CO.05 was considered significant. The sensitivity, specificity, positive predictive value, negative predictive value and predictive accuracy were defined as follows: sensitivity = true positive/(true positive + false negative], specificity = true negative/(true negative + false positive), positive predictive value = true positive/(true Fositive + false positive), negative predictive value = true negative/(true negative + false negative), and predictive accuracy = (true positive + true negative)/ total population, where true positive represents patients with inefficacy by the programmed stimulation criteria and subsequent clinical arrhythmic events, true negative represents patients with efficacy by the programmed stimulation criteria and no clinical arrhythmic events, false positive represents patients with inefficacy by the programmed stimulation criteria but no clinical arrhythmic event, and false negative represents patients with efficacy by the programmed stimulation but with subsequent clinical arrhythmic events.
Results Programmed stimulation: Results of programmed stimulation are summarized in Table I. At baseline before therapy, all patients, including 4 patients whose documented arrhythmias were VF, had a sustained monomorphic VT induced by programmed stimula-
1316
PROGRAMMED
TABLE II Criteria
Criterion I. Effective I. Ineffective Il. Effective Il. Ineffective Ill. Effective III. Ineffective
STIMULATION
Arrhythmia-Free
AND AMIODARONE
Survival
Rates by Three Efficacy
Efficacy assessments by programmed stimulation and Holter criteria: Efficacy of amiodarone in each patient was assessedby 3 programmed stimulation ef-
Months .--
No. of Pts
6
12 58 25 45 49 21
100% 81% 91% 81 % 86% 79%
Criteria I, II and Ill = programmed p values by the log-rank test.
12
16
90%
90% 78% 64% 78% 80% 79%
78% 84%
78% 80% 79% stimulation
24 ---_ 90% 78% 84% 78%
80% 79%
efficacy
criteria
p Value p = 0.2150 p = 0.2470 p = 0.3260 I, II and III.
ficacy criteria. By criterion I, amiodarone was effective in 12 patients (group 1) and ineffective in 58 (groups 2 to 4). By criterion II, amiodarone was effective in 25 patients (groups 1 and 2) and ineffective in 45 (groups 3 and 4). By criterion III, amiodarone was effective in 49 patients (groups 1 to 3) and ineffective in 21 (group 4). Results of follow-up: The mean duration of followup was 19.2 f 19.3 months (mean f standard deviation, range 1 to 68) in all. There were 16 recurrences or sudden deaths, 10 nonarrhythmic cardiac deaths and 4 deaths from noncardiac reasons during the entire follow-up period. From the results of follow-up, arrhythmia-free survival rates were generated by the Kaplan-Meier’s method and the differences were tested by the log-rank test (Fig. 1 to 3). The same results are also summarized in Table II. Patients with efficacy by programmed stimulation criteria I, II or III seem to have a better prognosis when compared to patients with inefficacy by programmed stimulation criteria I, II or III, especially during the first 6 months of followup. The differences, however, did not reach statistical significance (see Discussion section). From the results of follow-up, sensitivity, specificity, positive predictive value, negative predictive value and predictive accuracy of each criterion at 24 months were generated and are shown in Table III.
tion at the right ventricular apex requiring intervention for termination. Changes in the mode of VT induction produced by amiodarone therapy were analyzed. VT became noninducible in 12 patients (group 1) and harder to induce in 13 patients (group 2): from doubles to triples during sinus rhythm in 3 patients, from triples during sinus rhythm to triples during ventricular pacing in 2, from single to doubles during ventricular pacing in 1 patient, from single to triples during ventricular pacing in 1, and from doubles to triples during ventricular pacing in 6. Induction modes were unchanged in 24 patients (group 3) and easier in 21 (group 4): from triples to doubles during ventricular pacing in 11, from triples during ventricular pacing to triples during sinus rhythm in 2, from doubles to single during ventricular pacing in 3, from single during ventricular pacing to single during sinus Discussion rhythm in 1 patient, from triples to doubles during The results of this study suggest that: (1) Patients sinus rhythm in 1, from triples to single during sinus with efficacy by criterion I appear to have better progrhythm in 1, from doubles during ventricular pacing to noses when compared with patients with inefficacy. triples during sinus rhythm in 1, and from single dur- However, many patients with inefficacy by criterion I ing ventricular pacing to doubles during sinus rhythm had a good outcome (nonspecificity). (2) Two previousin 1. Because of our stimulation protocol calling for ly reported criteria (criteria II and III] based on the triples during sinus rhythm before singles or doubles changes in the mode of VT induction may not predict during ventricular pacing, the last 2 patients described clinical outcomes. (3) Criterion II is sensitive but nonspecific. Inefficacy by criterion II does not preclude a here were considered to have an easier induction. These 2 patients would have been considered to have good outcome. (4) Criterion III is specific but insensia harder or same induction by criteria used by other tive. Efficacy by criterion III does not preclude a poor investigators.*~‘l outcome.
jiFk-.-
k
4
.--.-.-.-.-
groupl(Efflcocy by PESI) group21lnefflcocy by PESI] p=O 2150
a-b.-.-
2
70-
y 2 c ;
605040-
-
-
.__._
by PEW) 2 / Inaff,caq by PESII)
group I (Eff,cocy
A-
-
group
p=O 2470 by logronk tert
v,
by logronk tw
-.-.-.-
3020loI 6 I2 Duration of Follow-up(months)
FIGURE 1. Arrhythmia-free lion criterion I (PES I).
survival
I I8
rates by programmed
I 24
0
I 12
I 6 Duratmn
slimula-
FIGURE 2. Arrhythmia-free tion criterion II (PES II).
I 18
I 24
of Follow-up(months)
survival
rates by programmed
stimula-
June
The mode of induction of VT by programmed stimulation may depend on several factors, such as the nature (especially refractory periods and conduction velocities] of the diseased tissue which is the substrate for potential reentry, the distance and conduction time from the stimulation site to the potential reentry circuit, and the refractory periods of the local myocardiurn at the stimulation site. After administration of an antiarrhythmic agent, the mode of induction of VT could change not only when the agent changes the nature of the potential reentry circuit, but also when it changes the refractory periods of local myocardium at the stimulation site or the conduction time from the site to the potential circuit. Therefore, the mode changes after drug administration may not reflect the effect of the agent on the potential circuit in some patients. In addition, the changes in the mode of induction may be due to spontaneous day-to-day variations’:(m”’ unrelated to antiarrhythmic agents. Beside these limitations, programmed stimulation cannot evaluate the effects of antiarrhythmic agents on the triggering mechanism, which may be an essential prerequisite for the initiation of tachycardia due to reentry or increased automaticity. Nademanee et al6 postulated that amiodarone may be effective despite persistent induction of arrhythmia by programmed stimulation because it abolishes the triggering mechanism for initiating VT rather than altering the substrate for reentry. Programmed stimulation protocol: Our protocol for programmed stimulation and patient selection criteria based on the programmed stimulation results at baseline are similar to those of other investigatorsR,‘“,” who have reported good predictive values of programmed stimulation in patients taking amiodarone. The 3 efficacy criteria used in this study are the same as those in other studies.H,“.‘7 Because of our stimulation protocol calling for 3 extrastimuli during sinus rhythm before 1 or 2 extrastimuli during ventricular pacing, the hierarchy used in this study is slightly different from others.s~11,17~18 Had we used their definitions, however, determination of mode changes would have been different in only 2 of 70 patients in our study by the criteria used by McGovern et aI8 and by Naccarclli et al,” and different in only 1 patient by the criterion of Wellens et alI7 (see results of programmed stimulation). Comparison of results of this and other studies: Mean loading dose and maintenance dose of amiodarone and the timing of programmed stimulation during amiodarone therapy in this study are similar to those of other studies.“~‘“~” Efficacy rates by programmed stimulation criteria in this study were similar to others.‘“,” The results of follow-up of all patients in this study are similar to those of McGovern et a18and of other studies,‘,“-” but somewhat better than those of Horowitz et aI’” and Naccarelli et al.‘l These findings suggest that the study population and method used in this study are probably similar to those of other studies, Conflicting results have been reported by various investigators regarding the values of ambulatory monitoring, 1'1 12 amiodarone blood leveP”“~‘- and reverse
11%.1987
THE
AMERICAN
JOURNAL
TABLE III Accuracies Two-Year Follow-Up
OF
CARDIOLOGY
of Three Criteria
Volume
1317
59
from the Results of
Criterion I
II
III
Sensitivity
92%
75%
33%
Specificity
17 %
26%
70%
Pos.
predictive
value
37%
35%
36%
Neg.
predictive
value
80%
67%
67 %
43%
43 %
67%
Predictive
accuracy
Tj level 25Z7in predicting clinical outcomes. Further studies are necessary to better identify patients with a high risk of recurrence during amiodarone therapy. Limitations of this study: Some patients in our study received an additional antiarrhythmic agent. Our results might have been different had we studied patients taking amiodarone alone. Many investigatorsl”~“~‘*~‘!’ including those cited in this study,‘“sl’ however, are using an additional antiarrhythmic agent in patients taking amiodarone, and antiarrhythmic efficacy in these patients is evaluated by programmed stimulation.ln,11,25’For this reason, our study may be relevant to the clinical management of patients with VT. Our study population included patients with arrhythmias refractory to other agents. Therefore, the results may not be applicable to other patient populations. When a patient had an inducible VT during amiodarone therapy, we did not repeat programmed stimulation the next day to confirm the reproducibility of programmed stimulation and the changes in the mode of induction. Therefore, the results of this study may have been due to the nonreproducibility (spontaneous day-to-day variation] of programmed stimulation protocol. Several investigators’3m16have studied the reproducibility of programmed stimulation and reported that the mode of induction of VT by programmed stimulation is not reproducible,‘“ml” even when the electrode catheters are replaced daily.” For this reason, we believe that the possible nonreproducibility of pro-
01
I 6 Durot~on
FIGURE 3. Arrhythmia-free tion criterion III (PES Ill).
I
I
I
12
18
24
of Follow-up
survival
(months)
rates by programmed
stimula-
1318
PROGRAMMED
STIMULATION
AND AMIODARONE
grammed stimulation is not a limitation of this study, odarone in patients with refractory ventricular tuchycordia. Am [ Cordiol but a limitation of programmed stimulation and of the 8.1985;55’375m379, McGovern B, Garan H, Malacoff RD, DiMarco JP, Grant G, Sellers D, changes in the mode of induction in assessing antiarRuskin IN. Long-term clinical outcome of ventricular tachycordio or fibrillotion treated with omiodorone. Am [ Cordial 1984;53:1558-1563. rhyth;nic agents. 9. Saksena S. Rothbart ST, Capello G. Chronic effects of omiodarone in A relatively small patient sample size is another patients with refractory ventricular tuchycordia. Int r Cardioll983;3:339-352. limitation. If the true survival proportions in the popu- 10. Horowitz LN, Greenspan AM, Spielman SR, Webb CR. Morganroth 1. Rotmensch H, Sokoloff NM, Rae AP. Segal BL, Kay HR. Usefulnessofelectrolations (of patients with efficacy and inefficacy by criphysiologic testing in evaluation of omiodorone theropy for sustained ventricterion I] are 90% and 60% or some more extreme com- ular tochyorrhythmios associated with coronury heart diseuse. Am / Cordiol bination, the probability of getting nonsignificant 1985;55:367-371. Naccarelli GV, Fineberg NS, Zipes DP, Heger ]I. Duncan G. Prystowsky results (as we did] from our sample size (12 patients 11. EN. Amiodorone: risk fuctors for recurrence of symptomatic ventricular with efficacy and 58 patients with inefficacy) with a Z- tachycurdia identified at electrophysiologic study. /ACC 1985;6:814-821. 12. Kim SG, Seiden SW, Mates ]A. Waspe LE. Fisher JD. Discordance betailed test and alpha equal to 0.05 is 28%. Therefore, tween ambulatory monitoring and programmed stimulation in assessing effiour study of efficacy criterion I has a statistical power cacy of class fA agents in the patients with ventricular tochycardio. [ACC of 7270, which is less than a customarily accepted sta- 1985;6:539-544. McPherson CA, Rosenfeld LE. Batsford WP. Day-to-day reproducibility tistical power of 80%. Studies of a larger sample size of13.responses to right ventricular programmed electrical stimulation: implicocould have revealed differences in surkival rates of tions for serial drug testing. Am / Cordiol 1985;55:689-695. patients with efficacy and inefficacy by criterion I. 14. Schoenfeld MH. McGovern B. Garan H. Ruskin JN. Long-term reproducof responses to programmed cardiac stimulation in spontaneous venWith regard to criterion II, with our sample size (25 ibility tricular tochyurrhythmios. Am [ Curdiol 1984;54:564-568. patients with efficacy by criterion II and 45 patients 15. Lombardi F, Stein J. Podrid PJ, Granboys TB. Lown BP. Doily reproducibility of electrophysiologic test results in malignant ventriculur arrhythmia. with inefficacy), the statistical power of our study is Am [ Cordiol 1986;57:96-101. greater than 80% (89%). With regard to criterion III, 16. Duff HI, Mitchell LB, Wyse DG. Programmed electrical stimulation studwith our sample size (49 patients with efficacy and 21 ies for ventricular tochycordio induction in humans. Il. Comparison of inelectrode catheter und daily catheter replacement. rACC l986;8: patients with inefficacy), the statistical power of our dwelling 576-581, study is also greater than 80% (86%). Therefore, the 17. Wellens HJl, Brugada P. Stevenson WG. Programmed electrical stimulasample sizes of our study may be adequate for assess- tion of the heart in patients with life-threatening ventricular arrhythmias. What is the significance of induced orrhythmios and what is the correct ing efficacy criteria II and III. If the difference in stimulotion protocol? Circulation 1965;72:1-7. survival proportion of true populations i&less than that 18. Klein LS, Fineberg NS, Heger JJ. Miles WM, Kammerling IM. Chang MS, DP. Prystowsky EN. Amiodorone: prospective evaluation ofo discrimistated previously (9070 vs 60%), studies of a larger Zipes nant function to predict recurrence of ventricular orrhythmios (obstr). Circusample size will be necessary to have a statistical pow- lation 1985;72:suppl III:IIf-273. er of 80%. Further studies of a larger sample size 19. DiCarlo LA, Morady F, Sauve MJ. Maone P, Davis JC, Evans-Bell T. Winston SA. Scheinman MM. Cardiac arrest and sudden death in patients should be done to confirm the results of this study. treated with amiodarone for sustained ventricular tachycardio or ventriculur Acknowledgment: We express our appreciation to ~~;br!t~;io-?s4~ stratification based on clinical variables. Am [ Cardiol Lawrence Krasnoff, PhD, for assistance in statistical 20. Marchlinski ’ FE, Buxton AE. Flores BT. Doherty JU, Waxman HL. Josephanalysis and Patti Garcia for secretarial assistance in son ME. Value of Holter monitoring in identifying risk for sustained ventricular urrhythmiu recurrence on amiodarone. Am \ Cardiol 1985;55:709-712. the manuscript preparation. 21. Veltri EP. Reid PR. Platia EV. Griffith LS. Amiodarone in the treatment of
References 1. Heger Jr. Prystowsky EN, Jackman WM. Naccarelli GV. Warfel KA, Rinkenberger RL, Zipes UP. Amiodorone: clinical efficacy and electrophysiology during long-term therapy for recurrent ventricular tachycardio or ventricular fibrillation. N Engl [ Med 1981;305:539-544. 2. Waxman HL, Groh WC, Marchlinski FE. Amiodarone for control of sustained ventricular tuchyorrhythmias: clinicul und electrophysiologic effects in 51 patients. Am 1 Cordiol 1982:50:1066-1074. 3. Nademanee K. Singh BN, Hendrickson 1. Intarachot V, Cannom DS. Lopez B, Feld G, Weiss 1. Stephenson W. Amiodorone in refructory life-threatening ventricular arrhythmius. Ann Intern Med 1983;98:577-584. 4. Haffajee CI, Love ]C. Canada AT, Lesko LJ, Asdourian G, Alpert IS. Clinical pharmocokinetics and efficacy of amiodarone for refractory tuchyarrhythmias. Circulation 1983;67:1347-1355, 5. Hamer AW, Finerman WB, Peter T, Mandel WJ. Disparity between the clinical und electrophysiologic effects of omiodorone in the treutment of recurrent ventricular tachyurrhythmios. Am Heart r 1981;1K?;992-1000. 6. Nademanee K, Hendrickson J, Kannar R, Singh BN. Antiorrhythmic efficacy and electrophysiologic actions of omiodorone in potients with life-threotnnmg ventricular orrhythmios: potent suppression of spontaneous occurring tachyarrhythmia versus inconsistent abolition of induced ventricular tochycordio. Am Neurt \ 1982;103:950-958. 7. Veltri EP. Reid PR, Platia EV, Griffith LSC. Results of lute progrommed electrical stimulation results and long-term electrophysiologic effects of om-
fife-threatening ventricular tochycordio: role of fiolter monitoring in predieting long-term clinicof efficacy. /ACC 1985:6:806-813. 22. Morady F, Scheinman MM, Hess DS. Amiodurone in the management of putients with ventricular tachycordia and ventricufor fibrillution. PACE 1983;6:609-615. 23. Mostow ND, Rakita L. Vrobel TR, Noon DL. Blumer J. Amiodorone: correlation of serum concentration with suppression of complex ventricular ectopy activity. Am [ Cardiol 1984;54:569-574. 24. Rotensch HH. Swanson BN. Greenspon AJ, Shoshani D. Greenspan AM. Amiodarone: individualizing dosoge with serum concentrations. PACE 1983;
&1327-1335. 25. Nademanee
K, Singh BN, Hendrickson ]A. Reed AW. Melmed S. Hershman 1, Pharmocokinetic significance of serum reverse T3 levels during omiodarone treutment: a potentiul method for monitormg chronic drug therapy. Circulution 1982;66:202-211. 26. McKenna WI, Krikler DM. Clinical evuluation of the efficacy of orul umiodurone. fir Heart r 1984X241-242. 27. Baerman 1, Morady F, DiCarlo L. Anne&y T, Foley MK. Nichlas J, Crevey B. Interrelationship between serum levels of amiodorone, desethylamidarone, and reverse ‘1’3 and amiodorone-induced (27’ prolongation (obstr). Circulatlon 1985;72:suppl fII:IIl-167. 28. Shea P. Schechtman K. Lal R. Kim SS, Ruffy R. Amiodarone-flecoinide interaction [ubstr). /ACC 1986;7:suppl A:93A. 29. Marchlinski FE, Buxton AE, Flares B. Pembrook-Rogers D, Josephson ME. Combined effects ofomiodarone and procainomide in patients with ventriculur tuchycordia [obstr). [ACC 1966;7:suppl A:llOA.
AND CONDUCTION DISTURBANCES
Prognostic Value of the Changesin the Mode of Ventricular TachycardiaInduction During Therapy with Amiodaroneor Amiodaroneand a Class 1A Antiarrhythmic Agent SO0 G. KIM, MD, SAMUEL D. FELDER, MD, ILONA FIGURA, MD, DEBRA R. JOHNSTON, RN, ANTHONY D. MERCANDO, MD, and JOHN D. FISHER, MD
78 % and 78 % in patients with inefficacy, respectively; and 80 % and 80 % in patients with efficacy by criterion Ill and 79% and 79% in patients with inefficacy, respectively (difference not significant for all). From the results of follow-up at 2 years, sensitivities of criteria I, II and Ill were 92 % , 75% and 33%, respectively. Specificities were 17%, 26 % and 70 % , respectively, and predictive accuracies were 43 % , 43 % and 67 % , respectively. Thus, patients with efficacy by criterion I appear to have a better prognosis when compared with patients with inefficacy. However, many patients with inefficacy by criterion I had a good outcome (nonspecificity). Criteria II and Ill based on the changes in the mode of VT induction may not predict clinical outcomes. Criterion II is sensitive but nonspecific and criterion Ill is specific but insensitive.
The prognostic value of 3 previously reported programmed stimulation efficacy criteria was studied in 70 patients taking amiodarone for sustained ventricular tachycardia (VT). At baseline all patients had VT inducible by programmed stimulation. After amiodarone loading (935 f 271 mg/day for I6 f 7 days), efficacy of amiodarone was determined by 3 programmed stimulation criteria (criterion I = VT not inducible or I5 beats or less; criterion II = VT not inducible or harder to induce; criterion Ill = VT not easier to induce). Amiodarone was effective in 12, 25 and 49 of 70 patients by criteria I, II and Ill, respectively. There were I6 recurrences or cardiac arrest during the follow-up period (I 9 f I9 months). Actuarial arrhythmia-free survival rates at I and 2 years were: 90 % and 90% in patients with efficacy by criterion I and 76% and 76% in patients with inefficacy, respectively; 64% and 84% in patients with efficacy by criterion II and
(Am J Cardiol 1987;59:1314-1318)
T
he role of programmed stimulation in assessing efficacy and inefficacy of amiodarone in patients with malignant ventricular arrhythmia is controversial.“l Many investigators1-7 have reported poor predictive values of programmed stimulation in patients taking From the Department of Medicine, Division of Glrtliology, Arrhythmia Service, Montefiorc h4edical Center-Mnntcfiore Hospital/Moses Division and the Albert Einstein College of Medicine, Bronx, New York. Manrwript rcceivcd October 20. 1986; rcvisctl mwuscript rcccivetl and accepted January 12. 1987. Address for reprints: SW G. Kim, MD, Division of Cardiob g>‘. Montcfiorc Mcdiwl Center. 111 East 210th Street, Bronx. New York loG7. 1314
amiodarone. Other investigatorsa-I1 however, reported that programmed stimulation is predictive in such patients. They suggested that certain changes in the mode of ventricular tachycardia [VT) induction produced by amiodarone therapy are predictive.8,10.1’Horowitz et allo reported that suppression of inducible VT with amiodarone predicts a good outcome compared with the results of patients with persistence of inducible VT, McGovern et al8 reported that if VT is no longer inducible or harder to induce by programmed stimulation, a patient will have a good outcome with amiodarone. Naccarelli et al,” however, reported that easier induction of VT predicts a poor outcome with amiodarone therapy. It is therefore un-
June 1, 1987
known which efficacy criterion is most predictive. TO compare the predictive values of 3 reported programmed stimulation efficacy criteria, we studied 70 patients taking amiodarone for recurrent sustained VT or ventricular fibrillation (VF). Efficacy of amiodarone in each patient was determined by these 3 programmed stimulation criteria.
Methods Patients: Seventy patients (54 men, 16 women, mean age 61 f 10 years] with recurrent, sustained VT with hemodynamic compromise (66 patients) or VF (4 patients] were studied. Fifty patients had coronary artery disease and 20 had idiopathic dilated cardiomyopathy. No arrhythmia was associated with an acute myocardial infarction or remediable causes (such as hypokalemia, digitalis toxicity or drug-induced arrhythmia). Criteria for admission to the study also included sustained VT by programmed stimulation requiring intervention for termination during a baseline study in the absence of antiarrhythmic agents. Patients with arrhythmias refractory to conventional nonexperimental drugs or patients with intolerable side effects from conventional drugs were entered into this study. Programmed stimulation: Programmed stimulation protocol used in this study has been rep0rted.l” Single, double or triple premature stimuli were introduced during sinus rhythm initially, then during ventricular pacing at cycle lengths of 600 to 400 ms. When VT could not be induced at the right ventricular apex, the stimulation protocol was repeated at the right ventricular outflow. The endpoint of stimulation was (1) induction of a sustained VT that required intervention for termination or (2) completion of the stimulation protocol. The modes of induction of VT at baseline and with amiodarone therapy in each patient were compared. Because of our stimulation protocol calling for 3 extrastimuli during sinus rhythm before 1 or 2 extrastimuli during ventricular pacing, the hierarchy of ease of induction was defined as follows: sinus rhythm + 1 extrastimulus, 2 extrastimuli, 3 extrastimuli, ventricular pacing + 1 extrastimulus, 2 extrastimuli and 3 extrastimuli. Three different programmed stimulation efficacy criteria reported to be predictive8,*0,‘1 were used. Amiodarone was considered effective when VT was no longer inducible or nonsustained (15 beats or less] (criterion I),“’ VT was noninducible or harder to induce compared with the baseline (criterion II),” or VT was not easier to induce (unchanged. with same mode of induction, harder or noninducible) [criterion III).l’ Study design: All patients gave informed consent before the study for serial drug testing by programmed stimulation and administration of amiodarone. All patients had a baseline programmed stimulation study at least 5 half-lives after discontinuation of all antiarrhythmic medications. Amiodarone was given orally twice daily in equally divided doses. All patients received a loading dose of amiodarone (935 f 271 mg/ day) for 16 f 7 days followed by a maintenance dose of
TABLE
THE AMERICAN
I
Results
JOURNAL
of Programmed
VT induction by SR SR SR VP VP VP
f + + + + +
OF CARDIOLOGY
1 2 3 1 2 3
No VT Inducible
Volume 59
1315
Stimulation
Pre-RX (No. of pts)
Post-Rx (No. of pts)
0 4 12 6 19 29
2 2 11 7 18 18 12
Rx = treatment; SR + 1, 2 or 3 = sinus rhythm + 1. 2 or 3 extrastimuli; VP + 1. 2 or 3 = ventricular pacing + 1, 2 or 3 extrastimuli; VT = ventricular tachycardia.
356 f 109 mg/day. Programmed stimulation was repeated at the end of amiodarone loading. In some patients with a hemodynamically significant VT inducible by programmed stimulation with amiodarone, a class 1A conventional antiarrhythmic agent (quinidine, procainamide or disopyramide) was added (18 patients)l” and programmed stimulation was repeated before discharge from the hospital. The endpoint of follow-up was recurrence of sustained VT or sudden death (death within an hour after the onset of symptom], other death, discontinuation of the discharge regimen because of adverse effects, or arrhythmia-free survival as of February 15, 1986. Statistical methods: The mean f standard deviation was used as the index of dispersion of observed values. The Kaplan-Meier’s method was used to generate actuarial survival rates of each group. The differences among groups were tested by the log-rank test for statistical significance. A Z-tailed p value -CO.05 was considered significant. The sensitivity, specificity, positive predictive value, negative predictive value and predictive accuracy were defined as follows: sensitivity = true positive/(true positive + false negative], specificity = true negative/(true negative + false positive), positive predictive value = true positive/(true Fositive + false positive), negative predictive value = true negative/(true negative + false negative), and predictive accuracy = (true positive + true negative)/ total population, where true positive represents patients with inefficacy by the programmed stimulation criteria and subsequent clinical arrhythmic events, true negative represents patients with efficacy by the programmed stimulation criteria and no clinical arrhythmic events, false positive represents patients with inefficacy by the programmed stimulation criteria but no clinical arrhythmic event, and false negative represents patients with efficacy by the programmed stimulation but with subsequent clinical arrhythmic events.
Results Programmed stimulation: Results of programmed stimulation are summarized in Table I. At baseline before therapy, all patients, including 4 patients whose documented arrhythmias were VF, had a sustained monomorphic VT induced by programmed stimula-
1316
PROGRAMMED
TABLE II Criteria
Criterion I. Effective I. Ineffective Il. Effective Il. Ineffective Ill. Effective III. Ineffective
STIMULATION
Arrhythmia-Free
AND AMIODARONE
Survival
Rates by Three Efficacy
Efficacy assessments by programmed stimulation and Holter criteria: Efficacy of amiodarone in each patient was assessedby 3 programmed stimulation ef-
Months .--
No. of Pts
6
12 58 25 45 49 21
100% 81% 91% 81 % 86% 79%
Criteria I, II and Ill = programmed p values by the log-rank test.
12
16
90%
90% 78% 64% 78% 80% 79%
78% 84%
78% 80% 79% stimulation
24 ---_ 90% 78% 84% 78%
80% 79%
efficacy
criteria
p Value p = 0.2150 p = 0.2470 p = 0.3260 I, II and III.
ficacy criteria. By criterion I, amiodarone was effective in 12 patients (group 1) and ineffective in 58 (groups 2 to 4). By criterion II, amiodarone was effective in 25 patients (groups 1 and 2) and ineffective in 45 (groups 3 and 4). By criterion III, amiodarone was effective in 49 patients (groups 1 to 3) and ineffective in 21 (group 4). Results of follow-up: The mean duration of followup was 19.2 f 19.3 months (mean f standard deviation, range 1 to 68) in all. There were 16 recurrences or sudden deaths, 10 nonarrhythmic cardiac deaths and 4 deaths from noncardiac reasons during the entire follow-up period. From the results of follow-up, arrhythmia-free survival rates were generated by the Kaplan-Meier’s method and the differences were tested by the log-rank test (Fig. 1 to 3). The same results are also summarized in Table II. Patients with efficacy by programmed stimulation criteria I, II or III seem to have a better prognosis when compared to patients with inefficacy by programmed stimulation criteria I, II or III, especially during the first 6 months of followup. The differences, however, did not reach statistical significance (see Discussion section). From the results of follow-up, sensitivity, specificity, positive predictive value, negative predictive value and predictive accuracy of each criterion at 24 months were generated and are shown in Table III.
tion at the right ventricular apex requiring intervention for termination. Changes in the mode of VT induction produced by amiodarone therapy were analyzed. VT became noninducible in 12 patients (group 1) and harder to induce in 13 patients (group 2): from doubles to triples during sinus rhythm in 3 patients, from triples during sinus rhythm to triples during ventricular pacing in 2, from single to doubles during ventricular pacing in 1 patient, from single to triples during ventricular pacing in 1, and from doubles to triples during ventricular pacing in 6. Induction modes were unchanged in 24 patients (group 3) and easier in 21 (group 4): from triples to doubles during ventricular pacing in 11, from triples during ventricular pacing to triples during sinus rhythm in 2, from doubles to single during ventricular pacing in 3, from single during ventricular pacing to single during sinus Discussion rhythm in 1 patient, from triples to doubles during The results of this study suggest that: (1) Patients sinus rhythm in 1, from triples to single during sinus with efficacy by criterion I appear to have better progrhythm in 1, from doubles during ventricular pacing to noses when compared with patients with inefficacy. triples during sinus rhythm in 1, and from single dur- However, many patients with inefficacy by criterion I ing ventricular pacing to doubles during sinus rhythm had a good outcome (nonspecificity). (2) Two previousin 1. Because of our stimulation protocol calling for ly reported criteria (criteria II and III] based on the triples during sinus rhythm before singles or doubles changes in the mode of VT induction may not predict during ventricular pacing, the last 2 patients described clinical outcomes. (3) Criterion II is sensitive but nonspecific. Inefficacy by criterion II does not preclude a here were considered to have an easier induction. These 2 patients would have been considered to have good outcome. (4) Criterion III is specific but insensia harder or same induction by criteria used by other tive. Efficacy by criterion III does not preclude a poor investigators.*~‘l outcome.
jiFk-.-
k
4
.--.-.-.-.-
groupl(Efflcocy by PESI) group21lnefflcocy by PESI] p=O 2150
a-b.-.-
2
70-
y 2 c ;
605040-
-
-
.__._
by PEW) 2 / Inaff,caq by PESII)
group I (Eff,cocy
A-
-
group
p=O 2470 by logronk tert
v,
by logronk tw
-.-.-.-
3020loI 6 I2 Duration of Follow-up(months)
FIGURE 1. Arrhythmia-free lion criterion I (PES I).
survival
I I8
rates by programmed
I 24
0
I 12
I 6 Duratmn
slimula-
FIGURE 2. Arrhythmia-free tion criterion II (PES II).
I 18
I 24
of Follow-up(months)
survival
rates by programmed
stimula-
June
The mode of induction of VT by programmed stimulation may depend on several factors, such as the nature (especially refractory periods and conduction velocities] of the diseased tissue which is the substrate for potential reentry, the distance and conduction time from the stimulation site to the potential reentry circuit, and the refractory periods of the local myocardiurn at the stimulation site. After administration of an antiarrhythmic agent, the mode of induction of VT could change not only when the agent changes the nature of the potential reentry circuit, but also when it changes the refractory periods of local myocardium at the stimulation site or the conduction time from the site to the potential circuit. Therefore, the mode changes after drug administration may not reflect the effect of the agent on the potential circuit in some patients. In addition, the changes in the mode of induction may be due to spontaneous day-to-day variations’:(m”’ unrelated to antiarrhythmic agents. Beside these limitations, programmed stimulation cannot evaluate the effects of antiarrhythmic agents on the triggering mechanism, which may be an essential prerequisite for the initiation of tachycardia due to reentry or increased automaticity. Nademanee et al6 postulated that amiodarone may be effective despite persistent induction of arrhythmia by programmed stimulation because it abolishes the triggering mechanism for initiating VT rather than altering the substrate for reentry. Programmed stimulation protocol: Our protocol for programmed stimulation and patient selection criteria based on the programmed stimulation results at baseline are similar to those of other investigatorsR,‘“,” who have reported good predictive values of programmed stimulation in patients taking amiodarone. The 3 efficacy criteria used in this study are the same as those in other studies.H,“.‘7 Because of our stimulation protocol calling for 3 extrastimuli during sinus rhythm before 1 or 2 extrastimuli during ventricular pacing, the hierarchy used in this study is slightly different from others.s~11,17~18 Had we used their definitions, however, determination of mode changes would have been different in only 2 of 70 patients in our study by the criteria used by McGovern et aI8 and by Naccarclli et al,” and different in only 1 patient by the criterion of Wellens et alI7 (see results of programmed stimulation). Comparison of results of this and other studies: Mean loading dose and maintenance dose of amiodarone and the timing of programmed stimulation during amiodarone therapy in this study are similar to those of other studies.“~‘“~” Efficacy rates by programmed stimulation criteria in this study were similar to others.‘“,” The results of follow-up of all patients in this study are similar to those of McGovern et a18and of other studies,‘,“-” but somewhat better than those of Horowitz et aI’” and Naccarelli et al.‘l These findings suggest that the study population and method used in this study are probably similar to those of other studies, Conflicting results have been reported by various investigators regarding the values of ambulatory monitoring, 1'1 12 amiodarone blood leveP”“~‘- and reverse
11%.1987
THE
AMERICAN
JOURNAL
TABLE III Accuracies Two-Year Follow-Up
OF
CARDIOLOGY
of Three Criteria
Volume
1317
59
from the Results of
Criterion I
II
III
Sensitivity
92%
75%
33%
Specificity
17 %
26%
70%
Pos.
predictive
value
37%
35%
36%
Neg.
predictive
value
80%
67%
67 %
43%
43 %
67%
Predictive
accuracy
Tj level 25Z7in predicting clinical outcomes. Further studies are necessary to better identify patients with a high risk of recurrence during amiodarone therapy. Limitations of this study: Some patients in our study received an additional antiarrhythmic agent. Our results might have been different had we studied patients taking amiodarone alone. Many investigatorsl”~“~‘*~‘!’ including those cited in this study,‘“sl’ however, are using an additional antiarrhythmic agent in patients taking amiodarone, and antiarrhythmic efficacy in these patients is evaluated by programmed stimulation.ln,11,25’For this reason, our study may be relevant to the clinical management of patients with VT. Our study population included patients with arrhythmias refractory to other agents. Therefore, the results may not be applicable to other patient populations. When a patient had an inducible VT during amiodarone therapy, we did not repeat programmed stimulation the next day to confirm the reproducibility of programmed stimulation and the changes in the mode of induction. Therefore, the results of this study may have been due to the nonreproducibility (spontaneous day-to-day variation] of programmed stimulation protocol. Several investigators’3m16have studied the reproducibility of programmed stimulation and reported that the mode of induction of VT by programmed stimulation is not reproducible,‘“ml” even when the electrode catheters are replaced daily.” For this reason, we believe that the possible nonreproducibility of pro-
01
I 6 Durot~on
FIGURE 3. Arrhythmia-free tion criterion III (PES Ill).
I
I
I
12
18
24
of Follow-up
survival
(months)
rates by programmed
stimula-
1318
PROGRAMMED
STIMULATION
AND AMIODARONE
grammed stimulation is not a limitation of this study, odarone in patients with refractory ventricular tuchycordia. Am [ Cordiol but a limitation of programmed stimulation and of the 8.1985;55’375m379, McGovern B, Garan H, Malacoff RD, DiMarco JP, Grant G, Sellers D, changes in the mode of induction in assessing antiarRuskin IN. Long-term clinical outcome of ventricular tachycordio or fibrillotion treated with omiodorone. Am [ Cordial 1984;53:1558-1563. rhyth;nic agents. 9. Saksena S. Rothbart ST, Capello G. Chronic effects of omiodarone in A relatively small patient sample size is another patients with refractory ventricular tuchycordia. Int r Cardioll983;3:339-352. limitation. If the true survival proportions in the popu- 10. Horowitz LN, Greenspan AM, Spielman SR, Webb CR. Morganroth 1. Rotmensch H, Sokoloff NM, Rae AP. Segal BL, Kay HR. Usefulnessofelectrolations (of patients with efficacy and inefficacy by criphysiologic testing in evaluation of omiodorone theropy for sustained ventricterion I] are 90% and 60% or some more extreme com- ular tochyorrhythmios associated with coronury heart diseuse. Am / Cordiol bination, the probability of getting nonsignificant 1985;55:367-371. Naccarelli GV, Fineberg NS, Zipes DP, Heger ]I. Duncan G. Prystowsky results (as we did] from our sample size (12 patients 11. EN. Amiodorone: risk fuctors for recurrence of symptomatic ventricular with efficacy and 58 patients with inefficacy) with a Z- tachycurdia identified at electrophysiologic study. /ACC 1985;6:814-821. 12. Kim SG, Seiden SW, Mates ]A. Waspe LE. Fisher JD. Discordance betailed test and alpha equal to 0.05 is 28%. Therefore, tween ambulatory monitoring and programmed stimulation in assessing effiour study of efficacy criterion I has a statistical power cacy of class fA agents in the patients with ventricular tochycardio. [ACC of 7270, which is less than a customarily accepted sta- 1985;6:539-544. McPherson CA, Rosenfeld LE. Batsford WP. Day-to-day reproducibility tistical power of 80%. Studies of a larger sample size of13.responses to right ventricular programmed electrical stimulation: implicocould have revealed differences in surkival rates of tions for serial drug testing. Am / Cordiol 1985;55:689-695. patients with efficacy and inefficacy by criterion I. 14. Schoenfeld MH. McGovern B. Garan H. Ruskin JN. Long-term reproducof responses to programmed cardiac stimulation in spontaneous venWith regard to criterion II, with our sample size (25 ibility tricular tochyurrhythmios. Am [ Curdiol 1984;54:564-568. patients with efficacy by criterion II and 45 patients 15. Lombardi F, Stein J. Podrid PJ, Granboys TB. Lown BP. Doily reproducibility of electrophysiologic test results in malignant ventriculur arrhythmia. with inefficacy), the statistical power of our study is Am [ Cordiol 1986;57:96-101. greater than 80% (89%). With regard to criterion III, 16. Duff HI, Mitchell LB, Wyse DG. Programmed electrical stimulation studwith our sample size (49 patients with efficacy and 21 ies for ventricular tochycordio induction in humans. Il. Comparison of inelectrode catheter und daily catheter replacement. rACC l986;8: patients with inefficacy), the statistical power of our dwelling 576-581, study is also greater than 80% (86%). Therefore, the 17. Wellens HJl, Brugada P. Stevenson WG. Programmed electrical stimulasample sizes of our study may be adequate for assess- tion of the heart in patients with life-threatening ventricular arrhythmias. What is the significance of induced orrhythmios and what is the correct ing efficacy criteria II and III. If the difference in stimulotion protocol? Circulation 1965;72:1-7. survival proportion of true populations i&less than that 18. Klein LS, Fineberg NS, Heger JJ. Miles WM, Kammerling IM. Chang MS, DP. Prystowsky EN. Amiodorone: prospective evaluation ofo discrimistated previously (9070 vs 60%), studies of a larger Zipes nant function to predict recurrence of ventricular orrhythmios (obstr). Circusample size will be necessary to have a statistical pow- lation 1985;72:suppl III:IIf-273. er of 80%. Further studies of a larger sample size 19. DiCarlo LA, Morady F, Sauve MJ. Maone P, Davis JC, Evans-Bell T. Winston SA. Scheinman MM. Cardiac arrest and sudden death in patients should be done to confirm the results of this study. treated with amiodarone for sustained ventricular tachycardio or ventriculur Acknowledgment: We express our appreciation to ~~;br!t~;io-?s4~ stratification based on clinical variables. Am [ Cardiol Lawrence Krasnoff, PhD, for assistance in statistical 20. Marchlinski ’ FE, Buxton AE. Flores BT. Doherty JU, Waxman HL. Josephanalysis and Patti Garcia for secretarial assistance in son ME. Value of Holter monitoring in identifying risk for sustained ventricular urrhythmiu recurrence on amiodarone. Am \ Cardiol 1985;55:709-712. the manuscript preparation. 21. Veltri EP. Reid PR. Platia EV. Griffith LS. Amiodarone in the treatment of
References 1. Heger Jr. Prystowsky EN, Jackman WM. Naccarelli GV. Warfel KA, Rinkenberger RL, Zipes UP. Amiodorone: clinical efficacy and electrophysiology during long-term therapy for recurrent ventricular tachycardio or ventricular fibrillation. N Engl [ Med 1981;305:539-544. 2. Waxman HL, Groh WC, Marchlinski FE. Amiodarone for control of sustained ventricular tuchyorrhythmias: clinicul und electrophysiologic effects in 51 patients. Am 1 Cordiol 1982:50:1066-1074. 3. Nademanee K. Singh BN, Hendrickson 1. Intarachot V, Cannom DS. Lopez B, Feld G, Weiss 1. Stephenson W. Amiodorone in refructory life-threatening ventricular arrhythmius. Ann Intern Med 1983;98:577-584. 4. Haffajee CI, Love ]C. Canada AT, Lesko LJ, Asdourian G, Alpert IS. Clinical pharmocokinetics and efficacy of amiodarone for refractory tuchyarrhythmias. Circulation 1983;67:1347-1355, 5. Hamer AW, Finerman WB, Peter T, Mandel WJ. Disparity between the clinical und electrophysiologic effects of omiodorone in the treutment of recurrent ventricular tachyurrhythmios. Am Heart r 1981;1K?;992-1000. 6. Nademanee K, Hendrickson J, Kannar R, Singh BN. Antiorrhythmic efficacy and electrophysiologic actions of omiodorone in potients with life-threotnnmg ventricular orrhythmios: potent suppression of spontaneous occurring tachyarrhythmia versus inconsistent abolition of induced ventricular tochycordio. Am Neurt \ 1982;103:950-958. 7. Veltri EP. Reid PR, Platia EV, Griffith LSC. Results of lute progrommed electrical stimulation results and long-term electrophysiologic effects of om-
fife-threatening ventricular tochycordio: role of fiolter monitoring in predieting long-term clinicof efficacy. /ACC 1985:6:806-813. 22. Morady F, Scheinman MM, Hess DS. Amiodurone in the management of putients with ventricular tachycordia and ventricufor fibrillution. PACE 1983;6:609-615. 23. Mostow ND, Rakita L. Vrobel TR, Noon DL. Blumer J. Amiodorone: correlation of serum concentration with suppression of complex ventricular ectopy activity. Am [ Cardiol 1984;54:569-574. 24. Rotensch HH. Swanson BN. Greenspon AJ, Shoshani D. Greenspan AM. Amiodarone: individualizing dosoge with serum concentrations. PACE 1983;
&1327-1335. 25. Nademanee
K, Singh BN, Hendrickson ]A. Reed AW. Melmed S. Hershman 1, Pharmocokinetic significance of serum reverse T3 levels during omiodarone treutment: a potentiul method for monitormg chronic drug therapy. Circulution 1982;66:202-211. 26. McKenna WI, Krikler DM. Clinical evuluation of the efficacy of orul umiodurone. fir Heart r 1984X241-242. 27. Baerman 1, Morady F, DiCarlo L. Anne&y T, Foley MK. Nichlas J, Crevey B. Interrelationship between serum levels of amiodorone, desethylamidarone, and reverse ‘1’3 and amiodorone-induced (27’ prolongation (obstr). Circulatlon 1985;72:suppl fII:IIl-167. 28. Shea P. Schechtman K. Lal R. Kim SS, Ruffy R. Amiodarone-flecoinide interaction [ubstr). /ACC 1986;7:suppl A:93A. 29. Marchlinski FE, Buxton AE, Flares B. Pembrook-Rogers D, Josephson ME. Combined effects ofomiodarone and procainomide in patients with ventriculur tuchycordia [obstr). [ACC 1966;7:suppl A:llOA.