Electrophysiologic predictors of long-term clinical outcome with amiodarone for refractory ventricular tachycardia secondary to coronary artery disease

ElectrophysiologicPredictors of Long-TermClinical Outcomewith Amiodaronefor Refractory Ventricular Tachycardia Secondaryto Coronary Artery Disease YOSHIZUMI

YAZAKI, MD, CHARLES I. HAFFAJEE, MB, MRCP, ROBERT L. GOLD, MD, RICHARD L. BISHOP, MD, and JOSEPH S. ALPERT, MD

Fifty-four patients. with a previous myocardial infarction and drug-refractory symptomatic ventricular tachycardia (VT) were treated with amiodarone on a long-term basis (range 6 to 54 months, mean 26) irrespective of the results of programmed ventricular stimulation, which was performed after high-dose oral amkxtarone loading for more than 4 weeks. VT was rendered noninducible in 6 of 54 patients (11% ) taking oral amiodarone. During a mean follow-up of 32 months, these 6 patients remained free of VT or sudden cardiac death. Forty-eight patients (69% ) continued to have VT inducible by programmed ventricular stimulation. However, they

could be separated into 2 groups: VT-modified (20 patients) and VT-unchanged (26 patients). In the VT-modified group, the induced VT with amiodarone was slowed or rendered nonsustained, and only 3 of 20 (15% ) patients during a mean follow-up of 23 months had well tolerated VT recurrences. In the VT-unchanged group, 16 of 26 patients (57 % ) had recurrences of VT or ventricular fibrillation during a mean follow-up of 24 months. Sudden cardiac death occurred in 6 of these 16 patients. Thus, programmed ventricular stimulation in patients with VT taking long-term amiodarone may have prognostic implications. (Am J Cardiol 1967;60:293-297)

A

miodarone hydrochloride, a benzofuran derivative originally developed as an antianginal agent1 and later discovered to have antiarrhythmic properties,z-4 has recently been shown to be effective for life-threatening ventricular tachycardia (VT] refractory to other antiarrhythmic agents. 5-g The prognostic value of programmed ventricular stimulation in the evaluation of amiodarone treatment for VT is increasingly being realized.10-14 However, the electrophysiologic changes that relate to outcome are not uniform.l4J5 Conventional methods of assessing drug efficacy are not easily applicable to amiodarone. Its pharmacokinetic profile is unusual and not fully understood, making it difficult to determine when steady state is achieved with this agent.7J6 Thus, the optimal oral dosing schedule both in terms of loading and maintenance dosages are based on clinical experience rather than predict-

able pharmacokinetics. Current clinical practice suggests that it may take several weeks of amiodarone loading before full clinical efficacy can be established.7J6 Twenty-four-hour ambulatory electrocardiographic monitoring to assess protection against VTventricular fibrillation (VF] with amiodarone therapy has also produced conflicting results.gJ0J5 Previous studies have suggested that programmed ventricular stimulation does not predict accurately the clinical recurrences of VT/VF during amiodarone therapy1°J5 compared with standard agents. This study reports the long-term outcome in 54 patients with previous myocardial infarction and documented life-threatening VT/VF treated with amiodarone as the only antiarrhythmic drug, irrespective of results of programmed cardiac stimulation.

From the Division of Cardiovascular Medicine, University of Massachusetts Medical Center, Worcester, Massachusetts. Manuscript received December 29, 1986; revised manuscript received and accepted March 23,1987. Address for reprints: Charles I. Haffajee, MD, Division of Cardiovascular Medicine, University of Massachusetts Medical Center, 55 Lake Avenue North, Worcester, Massachusetts 01605.

Patients and clinical characteristics: The study group consisted of 54 patients (50 men, 4 women) with coronary artery disease treated with amiodarone for clinically symptomatic and inducible monomorphic VT refractory to conventional antiarrhythmic agents. Mean age was 63 f 11 years (range 41 to 831. All patients had a previous myocardial infarction with left

Methods

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294

AMIODARONE

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ventricular ejection fractions ranging from 9 to 43% (mean 29.3). These were determined using nuclear angiography or recent cardiac catheterization. Clinically, 17 patients presented with sudden cardiac death (cardiovascular collapse within 1 hour of symptoms requiring cardiopulmonary resuscitation or cardioversion from VT/VF in the absence of acute myocardial infarction), 9 patients had syncope (transient loss of consciousness with spontaneous recovery), and 28 patients had symptomatic VT requiring intervention (light-headedness and weakness accompanying the arrhythmia). In no patient was the spontaneous ventricular arrhythmia related to acute ischemia, metabolic or electrolyte abnormalities, or the proarrhythmic effects of drugs. Quinidine, procainamide, disopyramide, propran0101, lidocaine, tocainide and mexiletine were ineffective either in the clinical setting in maximally tolerated dosages or at therapeutic blood levels in most of the patients before programmed cardiac stimulation. Despite a history of clinical drug failure, some of these antiarrhythmic drugs were tested singly and in combi-, nation during programmed cardiac stimulation before the patients received amiodarone. The efficacy of long-term amiodarone therapy was judged from clinical symptoms (syncope, palpitations], sudden cardiac death (fatal or resuscitated), and hospital admissions for recurrence of VT or results of 24hour ambulatory monitoring for sustained VT. Electrophysiologic studies: All 54 patients underwent complete programmed cardiac stimulation for VT induction. All antiarrhythmic agents were withheld for at least 5 half-lives before the control electrophysiologic study. Two to 3 multipolar intracardiac electrodes were inserted percutaneously into the right side of the heart through the femoral vein. A 7Fr tripolar catheter was positioned where adequate His bundle electrograms were recorded. A 6Fr quadripolar catheter was advanced to the high right atrium and programmed atria1 stimulation was performed, which included complete sinus and atrioventricular node evaluation. The quadripolar catheter was then advanced to the right ventricular apex and programmed ventricular stimulation, using stimuli of twice diastolic threshold at a rectangular pulse width of 2 ms, was performed using a programmable stimulator (Bloom Associates). During the study, we tried to induce sustained monomorphic VT (more than 30 seconds] by pacing at 2 basic cycle lengths (600 or 500 and 400 ms) and introducing 1 (S,), then 2 (S,S,), and finally 3 (S&&) ventricular extrastimuli until refractoriness was attained. This was also initially performed with the patient in sinus rhythm. The ventricular extrastimuli were scanned in diastole at lo-ms decrements in relation to the previous paced or sinus beat starting 50 ms beyond the refractory period (e.g., S1 S,]. If VT was not induced at the right ventricular apex, the catheter was advanced to the outflow tract of the right ventricle and the entire stimulation protocol was repeated. Left ventricular stimulation was used in patients whose VT was not inducible in the right ventricle. Surface leads

I, aVF, VI and 3 to 4 intracardiac recordings (filtered at 30 to 500 Hz] were amplified and recorded at paper speeds of 50 to 100 mm/s using a VR-12 (Electronics for Medicine/ Honeywell) recorder. The endpoint of the stimulation protocol was to induce the patients clinical VT reproducibly, and it had to be sustained (more than 30 seconds) unless hemodynamic deterioration prompted intervention. Induction of instantaneous polymorphic VT/VF requiring defibrillation was considered a nonspecific endpoint and not analyzed or subjected to drug testing. All patients underwent serial drug testing if they had reproducible monomorphic VT (more than 30 seconds] or VT requiring interruption, or both. Initially, several antiarrhythmic agents (quinidine, procainamide, disopyramide, propranolol, lidocaine, tocainide and mexilitine), irrespective of clinical results, were tested both singly and in combination. After failing standard agents in the laboratory, all patients were given amiodarone, and repeat programmed cardiac stimulation identical to baseline was performed more than 4 weeks after amiodarone loading (range 4 to 10 weeks, mean 6). Fourteen patients received digoxin and 1 received propranolol throughout the period of amiodarone administration. Amiodarone administration and follow-up: Amiodarone therapy was begun with a loading dose of 1,200 mg/day for 7 to 10 days, followed by 800 mg/day for the second week, then 600 mg/day for the third week. Thereafter, a maintenance dose of 400 mg/day was given to all patients until follow-up electrophysiologic study. In 12 patients, the dose was reduced to 200 mg/day during the maintenance phase because of the development of adverse effects. In patients previously taking digoxin the dose was reduced by half because of the known interaction of digoxin with amiodarone. We tried to record electrocardiographic documentation or 24-hour ambulatory electrocardiographic tracings of symptomatic episodes during follow-up. All patients had baseline chest x-ray film, electrocardiography, 24-hour electrocardiographic monitoring, antinuclear antibody titers, Tll, TB, thyroid-stimulating hormone, complete blood count, electrolytes, routine chemistry, urinalysis and complete ophthalmologic examination before initiation of amiodarone therapy. During the first year of amiodarone therapy, these tests were repeated every 3 months except for chest x-ray film, antinuclear antibody titers and eye examination, which were repeated at 6- to 12-month intervals. Ambulatory &hour electrocardiographic monitoring was obtained at least yearly or earlier if the patient had symptoms suggestive of arrhythmia. Recurrent arrhythmia was defined as sudden cardiac death or electrocardiographically documented symptomatic VT occurring at least 1 month after starting amiodarone. Statistical methods: Study variables were analyzed for statistical significance using the paired Student t test. A probability
August

TABLE I Unchanged

Comparison Groups

of Characteristics

of Patients

Noninducible No. of pts LVEF (%) Amiodarone dos (mg/day) Plasma concentration (mg/liter) Baseline VT-cycle 0-W d-RVERP

1.8 + 0.7 233

(ms)

44f

dos = dosage; d-RVERP ms; LVEF = left ventricular

al curves were obtained method.

= change ejection

f

THE AMERICAN

42” IO

Results Serial drug testing with conventional agents: Sustained symptomatic VT remained inducible in all 54 patients when tested with intravenous or oral procainamide or quinidine, propranolol, tocainide or mexiletine, singly and in combination. A mean of 2.4 drug trials was conducted in these patients. Programmed cardiac stimulation during chronic amiodarone: VT remained inducible in 48 of the 54 patients (89%] during long-term amiodarone therapy. The mean cycle length of the induced VT in these patients increased from 270 f 65 ms at baseline to 428 f 84 ms (p
OF CARDIOLOGY

VT-Unchanged

20 32 f 17 324 f 100 2.1 f

Volume

60

295

227

f

56t

34 f

26

p Value

28 29 f 13 363 f 79

0.7

in effective refractory period fraction; NS = not significant;

using the Kaplan-Meier

JQURNAL

in the

VT-Modified

6 31 f 17 367 f 82

length

I, 1987

1.9 f 289

f

31 f

of right ventricle VT = ventricular

NS NS

0.7

NS

71’7


23

NS

at a paced cycle tachycardia.

length

of 400

during a mean follow-up of 24 months (range 9 to 42). The mean daily maintenance dose of amiodarone in this group was 324 f 100 mg (range 200 to 400). Amio-, darone had to be discontinued in 2 patients because of reversible pulmonary fibrosis, which developed 35 and 9 months, respectively, after starting amiodarone. One patient died of congestive heart failure 11 months after initiation of amiodarone therapy and 1 patient declined long-term amiodarone. There were no sudden deaths in this group during follow-up. In the VT-unchanged group, symptomatic VT recurred in 16 of 28 patients (55%); 6 of these patients had sudden cardiac death (5 fatally] during a mean follow-up of 24 months (range 6 to 461. The mean daily maintenance dose of amiodarone was 363 f 49 mg (range 200 to 400). There were no discernible differences between the 3 groups with respect to ejection fraction, amiodarone daily dose or plasma concentration, or a combination of all 3, when single or multivariate analyses were performed. However, the baseline VT cycle length in patients from the VT-unchanged group was significantly longer than that for the VT-

! ~~;:~----------::~------------------~ c------------------------------------------*

c

(n= 16)

3 9 0.4.-? 5

.

-

4 0.2E

(n=9)

Non Inducible

e-m---+

VT Modtiled

-

VT Unchanged

Group Group

(6 pls) (20 pts)

Group

(28

pts)

3 O~,~,,,,,,,,,,,,,,,,~,,‘~,‘,,‘,,’,l,,i’,’, 0 5 10

15 Time

20

25

30

35

40

(Months)

FIGURE 1. Kaplan-Meier life-table analysis for patients in the noninducible, ventricular tachycardia (VT)-modified and VT-unchanged groups during amiodarone therapy. n = numbers of patients available for analysis.

296

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modified and VT-noninducible group (289 f f 56 vs 233 f 42 ms, p
Discussion

71

vs 227

senting symptom of syncope tended to produce a favorable long-term outcome in patients with VT treated with amiodarone. The reason for the apparent disparity between VT inducibility during programmed cardiac stimulation and clinical outcome of amiodarone therapy is still unknown. Some investigators suggestthat amiodarone works in some patients by abolishing the electrical trigger that initiates reentrant ventricular arrhythmia rather than by affecting the tachycardia circuit itself.10s20 Our study demonstrates that when amiodarone increases the VT cycle length and renders the VT hemodynamically stable, even without preventing its induction, a generally favorable outcome occurs during long-term follow-up. This observation suggeststhat amiodarone may also affect the properties (refractoriness and conduction velocity) of the reentrant VT circuit. We recognize that VT was rendered noninducible during programmed cardiac stimulation in only 11% of patients in this study, as opposed to a reported 20 to 30% noninducibility in other series. This may be a result of our aggressive programmed cardiac stimulation protocol rather than to inadequate amiodarone therapy. For the VT to be noninducible by programmed stimulation, patients had to be negative both at the apex and outflow of the right ventricle during multiple paced cycle lengths, with insertion of 3 premature ventricular extrastimuli, until refractoriness occurred regardless of the mode of VT induction during baseline study. Our amiodarone loading and maintenance schedules are similar to those used in other studies, and adequate plasma concentrations of amiodarone were observed in all 54 patients. Clinical implications: In this study, the overall clinical efficacy of amiodarone for suppressing VT was 63% despite continued inducibility of VT during pro-grammed cardiac stimulation in 89% of patients. However, during long-term amiodarone therapy, the results of programmed cardiac stimulation appeared to have predictive value in that patients with VT sup pression or significant modification of VT (increase in cycle length by more than 25% with hemodynamic tolerance or conversion to nonsustained VT) did well and justified continued treatment with amiodarone notwithstanding its long list of adverse effects. Adverse effects precluding long-term amiodarone therapy occurred in 4 of 54 patients (7%). However, in patients whose VT cycle length is unchanged from baseline or in whom VT acceleration occurs during ventricular premature stimulation with amiodarone, alternate or additional approaches to therapy (i.e., surgery, implantable cardiovertor-defibrillator or catheter ablation] should be considered because they have a high recurrence rate of VT and sudden cardiac death during long-term therapy with amiodarone alone.

Several studies suggest that programmed cardiac stimulation may be useful in identifying patients at risk for recurrent ventricular arrhythmias and sudden cardiac death during conventional antiarrhythmic drug therapy.lrJ8 However, with respect to amiodarone, some controversy still exists regarding the prognostic value of programmed cardiac stimulation during treatment of VT. Some early studies with short periods of follow-up show a discrepancy between clinical outcome and the results of programmed cardiac stimulation with amiodarone.lOJ1 Other studies, in particular those of Horowitz,13 NaccarellP4 and Borggrefe15 and their co-workers, suggestthat such studies may play a role in the long-term management of high-risk patients with recurrent VT treated with amiodarone. In contrast to this study, Heger et all9 did not find that a change in VT cycle length (VT slowing) was predictive of a good clinical outcome during programmed cardiac stimulation with amiodarone. However, variables such as change in repetitive ventricular response status,change in the mode of induction of VT, and the change in right ventricular effective refractory period or QT interval appeared to be better predictors of long term outcome with amiodarone in their study. McGovern et all2 suggestthat when VT is no longer inducible from the right ventricle with 2 extrastimuli or when VT is more difficult to induce during amiodarone therapy, clinical recurrences of VT do not occur. The shortcomings of most of these studies are that they used too few patients and with too short a followup, with the exception of the study of Horowitz et al.13 However, these studies do point out the potential usefulness of programmed cardiac stimulation during amiodarone therapy; they are generally in disagreement with other studies on the lack of usefulness of programmed cardiac stimulation during amiodarone therapy.lOJ5 The present study extends the observations on VT inducibility during programmed cardiac stimulation in relation to clinical outcome in those taking long-term oral amiodarone. Our study largely supports the observations of Horowitz et all3 with respect to patients whose VT was still inducible with amiodarone. However, we separated our patients with inducible VT into 2 groups. The patients whose VT was modified (VT cycle length increased by more than 25% or rendered nonsustained and self-limiting) did almost as well during long-term follow-up as our 6 patients in whom VT was no longer inducible during amiodarone therapy (Fig. 1). Moreover, results were poor in 28 patients in whom the induced VT was unchanged from baseline during long-term amiodarone therapy, with a 55% recurrence of symptomatic VT or sudden cardiac death, or both. In contrast to some of the reported studies, we did not find ejection fraction, mode References of VT induction, amiodarone dosage or plasma con- 1. Zelvelder WG. Investigation of the therapeutic activity centration predictive of VT suppression or long-term (cordarone] in the treatment of angina pectoris. Ear J outcome. However, we noted that a short baseline cy 1971;3:158-162. 2. Olsson SB, Brorson L, Varnauskas E. Class 3 antiarrhjrthmic cle length of the induced VT [rapid VT] and the pre- Observations from monophasic action potential recordings

of amiodorone Clin Pharmacol action in man. and amiodarone

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treatment. Br Heart j 1973;35:1255-1259. 3. Vaughan Williams EM. The discovery of the antiarrhythmic action of amiodarone. In: Amiodarone in Cardiac Arrhythmias. Royal Society of Medicine International Congress and Symposium Series, No. 16. Published jointly by Academic Press, Inc. (London] Ltd. and the Royal Society of Medicine, 1967:1-13. 4. Kaski JC, Girotti LA, Messuti H. Rutitzky B, Rosenbaum MB. Long-term management of sustained, recurrent, symptomatic ventricular tachycardia with amiodarone. Circulation 1981;64:273-279. 5. Heger J], 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 ventricuJar fibrillation. N Engl J Med 1981;305:539-545. 6. Waxman HL. Groh WC, Marchlinski FE, Buxton AE, Satowsky LM, Horowitz LN, losepbson ME, Kastor JA. Amiodarone for control of sustained ventricular tachyarrhythmias: clinical and electrophysialagic effects in 51 patients. Am j Cardial 1982;50:1066-1074. 7. Haffajee CI, Love JC, Canada AT, Lesko LJ, Asdourian G, Alpert JS. CJinical pharmacokinetics and efficacy of amiodarone for refractory tachyarrhythmias. Circulation 1983;67:1347-1355. 8. Nademanee K, Singh BN, Hendrickson J, Intrachat V, Lopez B, Feld G, Cannon D, Weiss JL. Amiodarone in refractory life-threatening ventricular arrhythmias. Ann Intern Med 1983;98:577-584. 9. Fagoros RN, Anderson KP, Winkle RA, Swerdlow CD, Mason JW. Amiadarone: clinical efficacy and toxicity in 96 patients with recurrent, drug refractory arrhythmias. Circulation 1983;68:88-94. 10. Hamer AW, Fineman WB, Peter T, Mandel WJ. Disparity between. the clinical and electrophysialogic effects of omiodarone in the treatment of recurrent ventricular tachyarrhythmias. Am Heart j 1981;102:992-1000. 11. McGovern B. Ruskin JN. The efficacy of amiodarone for ventricular arrhythmias can be predicted with clinical electraphysiologic studies. Int j Cardiol 1983;3:71-76.

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12. Horowitz LN, Greenspan AM, Spielman SR, Webb CR, Morganroth 1, Rotmensch H, Sokolaff NM, Rae AP, Segal BL, Kay HR. Usefulness of electrophysiologic testing in evaluation of amiodarone therapy for sustained ventricular tachyarrhythmias associated with coronary heart disease. Am j CardioJ 1985;55:367-371, 13. Nacarelli GV, Fineberg NS, Zupes DP, Heger JJ, Duncan G, Prystawsky EN. Amiodarone: risk factor for recurrence of symptomatic ventricular tachycardia identified at electrophysiologic study. jACC 1985;6:814-825. 14. Borggrefe M, Breithardt G, Seipel L. Value of serial electraphysiologic testing in the treatment of ventricular tachyarrhythmias with amiodarone (abstr). Circulation 1983;68:suppI rrI:rrr-281. 15. Nademanee K, Hendrickson J, Kannan R, Singh B. Antiarrhythmic efjicacy and electraphysiologic 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 1982;103:950-959. 16. Holt DW, Tucker GT, Jackson PR, Storey GCA. Amiodarone pharmacokinetics. Am Heart j 1983:106:840. 17. Mason JW, Winkle RA. Electrode-catheter arrhythmia induction in the selection and assessment of antiarrhythmic drug therapy for recurrent ventricular tachycardia. Circulation 1978;58:971-985. 18. Horowitz LN. Josephson ME, Farshidi A, Spielman SR, Michelson EL, Green span AM. Recurrent sustained ventricular tachycardia. III. Role of the electrophysialagic study in the selection of antiarrhythmic regimens. Circuiation 1978:58:986-997. 19. Heger JJ. Prystowsky EN, Zipes DP. Clinical efficacy of amiodarone dosage in treatment of recurrent ventricular tachycardia and ventricular fibrillation. Am Heart j 1983;106:887-893. 20. Veltri EP, Reid PR, Platia EV, Griffith LSC. Results of Jote programmed electrical stimulation and long-term electrophysialogic effects of amiodarone therapy in patients with refractory ventricular tachycardia. Am j Cardiol 1985;55:375-379.