Results of late programmed electrical stimulation and long-term electrophysiologic effects of amiodarone therapy in patients with refractory ventricular tachycardia

Results of Late Programmed Electrical Stimulation and Long-Term Electrophysiologic Effects of Amiodarone Therapy in Patients with Refractory Ventricular Tachycardia ENRICO P. VELTRI, MD, PHILIP R. REID, MD, EDWARD V. PLATIA, MD, and LAWRENCE SC.

GRIFFITH, MD

Thirteen patients with refractory, recurrent, lifethreatening ventricular tachycardia (VT) underwent electrophysiologic testing before and after long-term amiodarone therapy. Nine patients (69 % ) had coronary artery disease, 3 (23 % ) had nonischemic cardiomyopathy and 1 patient (8 % ) had mitral valve prolapse. At control electrophysiologic study, programmed electrical stimulation (PES) induced VT in all patients: sustained VT in 11 and nonsustained VT in 2 (9 beats and 31 beats). After oral loading with amiodarone, 1200 mg/day for 14 days, followed by maintenance therapy with 408 f 20 mg/day (mean f standard error of the mean), repeat PES at 6 f 1.6 months revealed inducible VT in 12 of 13 patients: sustained VT in 11 and nonsustained VT (32 beats) in 1 patient. Inducible VT was suppressed in only 1 patient. Amiodarone significantly increased sinus cycle length, PR interval, QRS duration and

right ventricular effective refractory period. Insignificant increases in AH, HV and QTc intervals were noted. At 24 f 2 months, 8 patients (62%) (all with inducible VT at late PES) were free of clinical arrhythmic events (syncope or sudden death), compared with 5 patients (38%) (4 with inducible VT at late PES) with events. There were no significant differences in the induced VT cycle length, VT cycle length change, ease of inducibility or hemodynamic response to induced VT at late PES in patients with and without arrhythmic events. Thus, in patients who receive long-term amiodarone treatment, late PES does not predict clinical efficacy, the frequency of conversion from inducible VT to noninducible VT is low, and despite ventricular electrical instability as judged by late PES testing, amiodarone is clinically effective in patients at high risk. (Am J Cardiol 1985;55:375-379)

Amiodarone, a benzofuran derivative originally developed as an antianginal agent1 and subsequently found to have potent ant&rhythmic properties,24 is effective in ventricular tachyarrhythmias.5-17 Many studies have revealed a disparity in clinical and electrophysiologic efficacy 12-15Ja21;others suggest a predictive role of programmed electrical stimulation (PES) in patients with ventricular tachycardia (VT) treated with amiodarone.22-24 The discrepancies among previously reported PES studies (which, for the most part, were performed within 1 to 2 months of starting amiodarone therapy) as well

as the unusual pharmacokinetic profile of the drug, namely an estimated half-life of many weeks,25y26 prompted the investigation of the role of late (after 6 weeks) PES testing in predicting long-term clinical efficacy and the electrophysiologic effect of chronic amiodarone therapy. Methods Patients: Thirteen patients (12 men, 1 woman) were referred to the Arrhythmia Servicefor the electrophysiologic evaluation of recurrent, life-threatening VT. Table I is a summary of the clinical characteristics. The mean age (& standard error of the mean) was 59 f 4 years (range 22 to 74). All patients had at least 1 episodeof documentedsustained VT (mean 3.5). Twelve patients had 2 or more episodes within 1 year of referral. The clinical presentations were sudden death (cardiovascular collapse within 1 hour of symptoms requiring cardiopulmonary resuscitation or cardioversion from VT/ventricular fibrillation in the absence of acute myocardial infarction) in 9, syncope (transient loss of consciousness with spontaneous recovery) in 3, and presyn-

From the Division of Cardiology, Department of Medicine, The Johns Hopkins Medical Institutions, Baltimore, Maryland. This study was supported in part by General Clinical Research Center Grant RR0003521 and the Outpatient General Clinical Research Center Grant RR00722-2, National Institutes of Health, Bethesda, Maryland. Manuscript received March 12, 1984; revised manuscript received September 17, 1984, accepted September 18, 1984. Address for reprints: Philip R. Reid, MD, Sinai Hospital, Belvedere at Greenspring Avenue, Baltimore, Maryland 21215. 375

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TABLE I

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Clinical Characteristics (n = 13)

Male Female Age Ejection fraction Ca$rd; substrate CAD, MI U& aneurysm MVP Clinical presentation Sudden death Syncope Presyncope Previous drugs failed Amiodarone dose (mglday) Loading Maintenance Follow-up (mo)

IN PATIENTS

ON AMIODARONE

of the Patient Population

TABLE II

12 59:4 32 f 4

Late PES

Control PES

10 1

;

Results of Control and Late Programmed Electrical Stimulation in Patients Receiving Amiodarone Treatment

:

Sustained VT Sustained VT Nonsustained VT Nonsustained VT

:

f 1 39

noncapture). PES was performed in at least 2 right ventricular (RV) sites (apex and outflow tract) and 2 LV sites (apex, septum or anterolateral wall) if sustained VT was not induced. Refractory periods were measured at the same paced cycle length and site of stimulation before and after therapy for purpose of comparison. Definitions: Nonsustained VT was defined as VT that was reproducible (2 of 3 attempts) L 3 repetitive ventricular beats that terminated spontaneously within 30 seconds and sustained VT as VT that lasted at least 30 seconds or required termination by ventricular overdrive pacing or external cardioversion due to hemodynamic compromise or degeneration into ventricular fibrillation. Noninducibility was defined as inability to induce VT at 2 RV and 2 LV sites using the protocol outlined above, and ease of inducibility was assessedby comparing the mode of extrastimulation and number of sites tested in control vs late PES testing. Easier induction required fewer extrastimuli (i.e., SrSs VS&S&s VS VbUr&)or fewer Sik?S tested (i.e., RV apex vs RV apex + RV outflow tract, or RV site vs LV site) to induce VT. Amiodarone administration: Physical examination, 12-lead electrocardiography, 24-hour Holter monitoring, complete blood count, basic chemistry screen including liver function tests, thyroid function tests, and ophthalmologic evaluation with slit-lamp examination were performed. All patients gave informed consent before amiodarone administration. Twenty-four-hour Holter monitoring (Avionics model 445B) was performed using dual-channel recordings. The magnetic tapes were analyzed using a Del Mar Avionics model 660 Dynamic Electrocardio [email protected] tapes were reviewed by at least 2 of the investigators and VT was defined as at least 3 repetitive ventricular beats at a rate of more than 100 beats/mm. The oral loading dose was 1,200mg/day for 14 days and the maintenance dose ranged from 200 to 800 mglday (mean 408 f 20). In no patient was another antiarrhythmic agent added after control PES study. Follow-up: Patients were followed in the Sudden Death Prevention Clinic at 2,3,4,6,9 and 12 months after discharge and every 6 months thereafter. Interim recurrent clinical arrhythmic events (syncope, sudden death or AICD discharge) and any adverse side effects were recorded. In casesof AICD discharge, the first discharge was considered a sudden death event for that patient. Physical examination, 12-lead ECG, 24-hour Holter, and repeat baseline blood studies were obtained at each visit. In addition, an external analyzer (AID CHECK, Intec Systems) was used to determine the number of AICD discharges delivered. Amiodarone efficacy: We defined efficacy of amiodarone based on the absence of clinical arrhythmic events after starting amiodarone. Amiodarone was considered to be effective if the patient remained free of clinical arrhythmic event through follow-up. Statistical analysis: The data are presented as mean f standard error. Data were tested for significance by paired and unpaired Student t tests; a p value <0.05 was accepted as the limit of significance.

1,200 408 f 20 24 f 2

CAD = coronary artery disease; CCM = congestive cardiomyopathy; MI = myocardial infarction; MVP = mitral valve prolapse.

cope (light-headedness accompanying the arrhythmia) in 1 patient. The underlying cardiac substrate, determined by cardiac catheterization and echocardiography, was coronary artery disease (defined by at least 70% coronary artery narrowing) in 9 patients (69%), nonischemic congestive cardiomyopathy (defined by diffuse left ventricular [LV] dysfunction with ejection fraction [EF] of 40% or less) in 3 patients (23%), and mitral valve prolapse in 1 patient (8%). Mean EF was 32 f 4% (range 10 to 51%). All patients with coronary artery disease had previous myocardial infarction and 2 patients had LV aneurysm. In 11 patients, an automatic internal cardioverter-defibrillator (AICD, Intec Systems) had been placed. Treatment with 5 f 0.4 previous drugs (range 3 to 8) had failed, defined as symptomatic arrhythmia recurrence, continued spontaneous VT on 24-hour Holter monitoring, VT induction by PES, or intolerable side effects from drugs. In all but 1 patient, treatment with at least 1 previous experimental antiarrhythmic agent (mean 1.6 drugs) had failed. Electrophysiologic study: Control electrophysiologic study was performed after treatment with all antiarrhythmic agents (other than digoxin and P-blocking drugs) had been discontinued for 48 hours. Late PES (at least 6 weeks after amiodarone therapy started) was performed in all patients. All patients who received digoxin or P-blocking drugs during the control study continued to receive them to the time of late study. Each patient gave informed consent for the study. Electrophysiologic studies were performed with the patient in the postabsorptive, nonsedated state. Standard quadripolar electrode catheters (lo-mm interelectrode distance) were inserted through the femoral, brachial or subclavian veins; the right femoral artery was cannulated for hemodynamic monitoring and for LV stimulation if necessary. Programmed ventricular stimulation was performed using a digital stimulator that delivers rectangular pulses 1 ms in duration at twice diastolic threshold (less than 4 mA). Surface leads 1, avF, VI, Vg and intracardiac electrograms were simultaneously displayed on an oscillographic recorder (Electronics for Medicine VR-16). Analog data were displayed on a spray-ink recorder (Mingograf) for real-time analysis at paper speeds of 25,50 and 100 mm/s and stored on magnetic tape for retrieval. Programmed ventricular stimulation was performed using single (SrSs) and double (&S&J extrastimuli at 3 basic ventricular pacing cycles (SrSr) (600,500,450 ms), followed by rapid ventricular decremental burst pacing (VbU&O consecutive beats at decreasing cycle lengths until 2:l pacing

stimulation;

Sustained VT Noninducible Sustained VT Nonsustained VT

PES = programmed tachycardia.

5 : 0.4

electrical

10 1

VT = ventricular

February

TABLE Ill

Control and Late Electrophysiologic Variables in Seven Patients Treated with Amiodarone Alone Control

Ft QRS QTc

785 f 173 f 99% 441 f 100 f 57 f 250 f

Late

50 a 11 14 4 a 11

a95 f 198 f 114f 471 f 107 f 65 f 277 f

p Value 44 II 13 20 a 5 14

p <0.025 p <0.005 p <0.05 NS D <0.025

All values are in milliseconds. NS = not significant; RV-ERP = right ventricular effective refractory period

Results Control electrophysiologic study: At control electrophysiologic study, VT was induced in all patients: sustained VT in 11 and nonsustained VT in 2 (9 beats and 31 beats). The morphologic characteristics of the VT (bundle branch pattern and axis) were identical in all instances to the spontaneous clinical VT noted on 12-lead electrocardiogram or dual-channel Holter monitor. The induced VT cycle length ranged from 165 to 405 ms (mean 268 f 16). Ten patients had VT induced on the right side (SrSs: 4; SiSsSs: 4; Vburst:2); in 3 patients VT was induced from the left ventricle (all using SiSsSs mode). Late electrophysiologic Study: Late PES testing was performed in all patients at 6 f 1.6 months (range 6 weeks to 15 months) after starting amjodarone. VT was induced in 12 patients: sustained VT in 11 and nonsustained (32 beats) in 1 patient. Again, in all instances the morphologic characteristics of the VT were identical to the spontaneous clinical VT. The induced VT cycle length ranged from 202 to 465 ms (mean 324 f 21). Ten patients had VT induced on the right side (SiSs: 2; 2) and 2 patients required left vensls2s3: 6; Vburst: tricular stimulation to induce VT (both using SiSsS3 mode). Table II is a summary of the results at both control and late PES. Of the 11 patients with inducible sustained VT at control study, only 1 patient had VT suppressed at late PES. One patient with inducible nonsustained VT (31 beats) at control study had sustained VT induced at late study. The other patient with inducible nonsustained VT (9 beats) at control study had nonsustained VT (32 beats) induced at late study. The VT cycle length at late study compared to control study was significantly increased (324 f 21 vs 268 f 16 ms, p
1, 1985

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TABLE IV

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Comparison of Patients With and Without Clinical Arrhythmic Events Nonevent

Event

No. of pts 5 Ejection fraction 36f 5 30:5 Inducible VT (late PES) VT cvcle lenath (late PES) 333:20 311:52 VT cycle length change ’ 65 f 16 85 f 22 Systolic BP response to VT 50f 16 43f 19 (control PES) Systolic BP response to VT (late PES) 65 f 15 53 f 11 Change in RVERP 24 f 5 20 f3 Ease of VT inducibility Unchanged Easier ; : More difficult 3 1

p Value NS NS NS NS NS NS

BP = blood pressure; NS = not significant; PES = programmed electrical stimulation; RVERP = right ventricular refractory period; VT = ventricular tachycardia.

P-blocking drugs) in whom intracardiac conduction times and RV effective refractory periods (ERP) at control and late study could be compared. Table III is a summary of the findings. Amiodarone significantly increased sinus cycle length (RR), PR interval, QRS duration and RVERP. Holter monitoring: All patients had documented spontaneous nonsustained VT when not receiving antiarrhythmic agents (other than digoxin and P-blocking drugs) on the baseline 24-hour Holter recording. Patients had 9.7 f 1.2 twenty-four-hour Holter recordings after 1 week of therapy through follow-up. Spontaneous nonsustained VT was completely suppressed in 7 patients (54%). Three patients without subsequent clinical arrhythmic events had nonsustained VT on any follow-up Holter (4 of 30 total Holter recordings). Three patients with subsequent events had nonsustained VT on any follow-up Holter (8 of 34 total Holter recordings). In each instance, nonsustained VT was 3 to 10 beats and asymptomatic. Clinical efficacy: At 24 f 2 months of follow-up (range.4 to 38), 8 patients (62%) were free of clinical arrhythmic events. All of these patients had inducible sustained VT at both control and late PES. Of the 5 patients (38%) with clinical arrhythmic events, 4 had inducible VT (3 sustained VT, 1 nonsustained VT) at late study. Clinical arrhythmic events manifested as recurrent sudden death in 4 patients (3 had AICD discharges with successful cardioversion-defibrillation) and syncope in 1 patient. Of the 11 patients with inducible sustained VT at late study, only 3 patients (27%) had clinical arrhythmic events. Table IV is a summary of the findings in patients with and without clinical arrhythmic events. There were no significant differences in VT cycle length, VT cycle length change, easeof VT inducibility, or hemodynamic response to induced VT at late PES in patients with or without arrhythmic events. Likewise, there were no significant differences in these variables in a subset analysis that excluded patients with inducible nonsustained VT at either control or late PES. Nine patients (69%) were alive at follow-up. Four patients died: 2 suddenly and 2 from refractory heart failure. The mean EF in the surviving patients was significantly better than that in patients who died, 37

378

PROGRAMMED

STIMULATION

TABLE V

IN PATIENTS

ON AMIODARONE

Comparison of Programmed Electrical Receiving Amiodarone Treatment No. of Pts

Heger et al’* Waxman et ali3 Nademanee et ali4 Haffajee et ali5 Hamer et al’s Nademanee et alI9 Waxman*O Groh et aI*’ McGovern & Ruskin** Saksena et al23 Saksena et a124 Present studv

19 zi

20 9

13

58

PES 2-4 wk 2-108 days 2 wk 3-34 wk 7-20 wk 14-56 days 7-210 days ? 8-42 days 21-88 days 21-81 days 1.5-15 mo

Stimulation

Studies in Patients

Inducible

Follow-Up

18 (95%)

12.7 8.6 15.0 6.8 15.0 12.0 12.0 2-9 12.5 3.5 2.5-20 24

7 (78%) 4(31%)

12 (92%)

mo mo mo mo mo mo mo mo mo mo mo mo

Events* 6 (33%) 23 (50%)+ 3 (207%) 8 26 (52%) 8 (5;%)t n 6 (50%)9 4 (33%)

* Number and percent of patients in whom VT could be induced with clinical arrhythmic events. 7 Represents patients with clinical arrhythmic events of total population. t Represents only patients who had VT as easily or more easily induced compared to control study. * Includes 5 patients who had clinical VT recurrence and 1 patient who had morphologically new arrhythmia induced. PES = programmed electrical stimulation; VT = ventricular tachycardia.

f 3% vs 19.5 f 5% (p
ducible sustained VT at late PES had clinical arrhythmic events. Similarly, only 2 of 10 patients with inducible sustained VT at both control and late PES studies had events. The only converter from inducible VT to noninducible in our series had recurrent spontaneous VT with syncope at 15 months of therapy. Although we have reported AICD discharges during supraventricular tachyarrhythmias,sl none of the patients with AICD discharges in the present study had histories of supraventricular tachyarrhythmias and the premonitory symptoms before AICD discharge were always similar to previous episodes of VT. Thus, we feel that AICD discharge was justified as an endpoint event. McGovern and Ruskin, using a grading system similar to ours to determine the easeof VT inducibility, reported that long-term clinical outcome was predicted by the PES results in 77% of patients. In the present study, the easeof VT induction was variable in patients with and without events and, thus, was not predictive. This is in agreement with the findings of Waxman et a1,13who demonstrated the failure of amiodarone to alter the easeof VT induction in any consistent fashion at shorter follow-up study time. Amiodarone lengthens the action potential duration, prolongs refractoriness and slows impulse conduction in ventricular myocardium.3 As noted in earlier studies, the VT cycle length in most patients was prolonged. Similarly, the RVERP was lengthened by ll%, which is within the 8 to 23% range noted previously.12-14J8Jg~22~24~27~32 However, there were no significant differences in VT cycle length, VT cycle length change, or RVERP change comparing patients with and without clinical arrhythmic events at follow-up. Therefore, amiodarone clearly has effects on electrophysiologic characteristics of ventricular tissue and on the induced VT rate, but these effects do not appear to correlate with clinical outcome. This leads to the speculation that most patients still have the vulnerability for sustained VT, but that the protective mechanism may lie in suppression of ventricular ectopic activity or abolition of triggers that initiate clinically important ventricular arrhythmias.

February

Although nonclinical morphologic forms of ventricular tachyarrhythmias in addition to the clinical spontaneous forms can be induced by PES,33 in our series only clinical VT morphologic patterns were induced. This is in contrast to the findings of Saksena et a1,24 who reported that in 42% of patients receiving chronic amiodarone therapy, morphologically new ventricular tachyarrhythmias were induced by PES. These investigators used a much more aggressive stimulation protocol. Differences in patient populations, amiodarone loading and maintenance dosage, interval between control and follow-up electrophysiologic study, programmed stimulation protocols, and definitions of induced VT may account for the discrepancies between our PES findings and those of previous studies. Clinical efficacy: At 24 f 2 month follow-up, 62% of the patients were free of clinical arrhythmic events. This degree of efficacy concurs with that of most previous studies,6,gJ0-13J6b ut is somewhat less than that Again, discrepancies in efreported by others. 5,7,8~14~15 ficacy can be accounted by differences in patient populations, drug dosage, duration of therapy, and definitions of efficacy. Our patients had a mean 3.5 episodes of sustained VT in the year preceding referral and 92% had failed at least 1 previous experimental agent (mean 1.6). Thus, the efficacy rate of 62% may reflect the response in a group of patients at exceptionally high risk. Although overall LV function (EF) did not predict clinical arrhythmic events, the mean EF certainly was worse in patients who later died from a cardiac cause. This concurs with the findings of Swerdlow et a1,34who reported overall LV function as an important determinant of survival from cardiac death in patients with ventricular tachyarrhythmias. Side effects: In our series, significant side effects were noted in 31% of patients, yet only 8% required drug withdrawal. These findings are consistent with most previous studies.5-8~10-12,14~15 Conclusions: We conclude that although amiodarone

is an effective, fairly well-tolerated

antiarrhythmic

agent in patients with refractory, recurrent VT, late PES testing does not predict clinical efficacy. Indeed, the frequency of Conversion from inducible VT to

noninducible VT is low. Further insight into the protective action of amiodarone may be achieved by efforts aimed at understanding the triggering mechanisms for onset of spontaneous ventricular tachyarrhythmias. Acknowledgmenti

We expressour gratitude to Sandra

Waclawski, RN, Sarah Ord, BS, Katherine Critikos and Jenny Beeker for technical support, to Toni Haase for secretarial assistance,and to Myron L. Weisfeldt, MD, for his thoughtful critique of the manuscript. References Vastesager M, Gillot P, Rasson G. Etude clinique d’une nouvelle medication antiangoreuse. Acta Cardiol 1967;22:483-500. Charlier R, Delaunois G, Bauthier J, Deltour G. Recherches dans la serie des benzofurannes. XL. Proprietes antiarrhythmiques de I’amiodarone. Cardiologia 1969;54:82-90. Singh BN, Vaughan Williams EM. The effect of amiodarone, a new antiangina1 drug, on cardiac muscle. Br J Pharmac 1970;39:657-667. Vaughan Williams EM. Classification of antiarrhythmic drugs. In: Symposium

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11. i?aski-jC; Girotti LA, Messuti H, Rutitzky B, Rosenbaum MB. Long-term management of sustained, recurrent, syniptomatic ventricular tachcardia with amiodarone. Circulation 1981:64:273-279. 12. 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 Engl J Med 1981;305:539-545. 13. Waxman HL, Groh WC, Marchlinski FE, Buxton AE, Sadowsky LM, Horowitz LN, Josephson ME, Kastor JA. Amiodarone for control of sustained ventricular tachyarrhythmias: clinical and electrophysiologic effects in 51 patients. Am J.Cardiol 1982;50:1066-1074. 14. Nademanee K, Singh BN! Hendrickson J, lntarachot V, Lopez B, Feld G, Cannon D, Weiss JL. Amlodarone in refractory life-threatening ventricular arrhythmias. Ann Int Med 1983;98:577-584. 15. Haffajee Cl, Love JC, Canada AT, Lesko LJ, Asdourian G, Alperl JS. Clinical pharmacokinetics and efficacy of amiodarone for refractory tachyarrhythmias. Circulation 1983;67:1347-1355, 16. Fogoros RN, Anderson KP, Winkle RA, Swerdlow CD, Mason JW. Amiodarone: clinical efficacy and toxicity in 96 patients with recurrent, drugrefractory arrhythmias. Circulation 1983;68:88-94. 17. Rakita L, Sobol SM. Amiodarone in the treatment of refractory ventricular arrhythmias. Importance and safety of initial high-dose theiapy. JAMA 1983:250:1293-1295. 10. Ham& AW, Finerman WB, Peter T, Mandel WJ. Disparity between the clinical and electrophysiologic effects of amiodarone in the treatment of recurrent ventricular tachyarrhythmias. Am Heart J 1981;102:9921000. 19. Nademanee K, Hendrickson J, Kannan R, Singh B. Antiarrhythmic efficacy and electrophysiologic actions of amicdarone in patients with life-threatening ventricular arrhythmias: potent suppression of spontaneously occurring tachyarrhythmias versus inconsistent abolition of induced ventricular tachycardia. Am Heart J 1982;103:950-959. 20. Waxman HL. The efficacy of amiodarone for ventricular arrhythmias cannot be predicted with clinical electrophysiologic studies (editorial). Int J Cardiol 1983;3:76-80. 21. Groh WC, Kastor JA, Josephson ME, Horowitz LN. Amiodarone: an effective drua for refractorv ventricular tachvcardia (abstr). Circulation 1980;62:suijpl lll:lll-152. . 22. McGovern B, Ruskin JN. The efficacy of amiodarone for ventricular arrhythmias can be predicted with clinical electrophysiologic studies (editorial). lnternat J Cardiol 1983;3:71-76. effects of ami23. Saksena S, Rothbart S, Kaufman W. Electrophysiologic odarone in refractory ventricular tachycardia (letter). N Engl J Med 1981; 305:1588. 24. Saksena ST Rothbart ST, Cappello G. Chronic effects of amiodarone in patients wdh refractory ventricular tachycardia. Int J Cardiol 1983;3: 339-352. 25. Broekhuysen J, Laurel R, Sion R. Recherches dans la serie des benzofurannes. XXXVII. Etude comparee du transit et du metabolisme de I’amiodarone chez diverses esoeces animales et chez I’homme. Arch Int Pharm Ther 1969;177:340-359,’ 26. Kannan R, Nademanee K, Hendrickson JA. Plasma levels of amiodarone and its elimination half-life following acute and chronic dosing in patients with ventricular arrhythmias. Circulation 1981;64:suppl IV:IV-264. 27. Finerman WB, Peter CT, Mandel WJ. Studies on the electrophysiologic &$ts of amiodarone In man. (abstr). Circulation 1980;62:suppl lll:lll28. Mason JW, Windle RA. Electrode-catheter arrhythmia induction and the selection and assessment of antiarrhythmic drug therapy for recurrent ventricular tachycardia. Circulation 1978;58:971-985. 29. Horowitz LN, Josephson ME, Farshidi A, Spielman SR, Michelson EL, Greenspan AM. Recurrent sustained ventricular tachycardia. 3. Role of the electrophysiologic study in selection of antiarrhythmic regimens. Circulation 1978;58:986-997. 30. Ruskin JN, DiMarco JP, Garan H. Out-of-hospital cardiac arrest. Electrophysiologic observations and selection of long-term antiarrhythmic therapy. N Engl J Med 1980;303:607-613. 31. Reid PR, Mower MM, Mirowski M, Watkins L, Juanteguy J, Platia EV, Griffith LSC. Correction of atrial tachyarrhythmias with the automatic imp/f;table cardioverter-defibrillator (abstr). Circulation 1984;68:suppl Ill: 32. Hamer AW, Mandel WJ, Zaher CA, Karagueuzin HS, Peter T. The electrophysiologic basis for the use of amiodarone for treatment of cardiac arrhythmias. PACE 1983;6:784-794. 33. Reddy CP, Sartini JC. Nonclinical polymorphic ventricular tachycardia induced by programmed cardiac stimulation: incidence mechanisms and clinical significance. Circulation 1980;62:988. 34. Swerdlow CD, Winkle RA, Mason JW. Determinants of survival in patients with ventricular tachyarrhythmias. N Engl J Med 1983;308:1436-1442.