Amiodarone for sustained ventricular tachycardia: Efficacy, safety, and factors influencing...

CURl?lCUtUM IN CARDIOLOGY

Amiodarone for SUM ventricular

tachycardia: Efficacy, safety, and factors influencing long-term outcome

Jerry L. Bauman, Pharm.D., Steven I. Berk, Pharm.D., Robert J. Hariman, M.D., Patricia W. Langenberg, Ph.D., Barbara J. Deal, M.D., Karen Beckman, M.D., Sheldon Brownstein, M.D., and Jose Gallastegui, M.D. Chicago, Ill.

The treatment of recurrent sustained ventricular tachycardia is difficult because traditional and investigational antiarrhythmic agents are frequently ineffective or result in intolerable side effects limit- ing long-term therapy.le4 Many patients with this arrhythmia eventually require empiric therapy with amiodarone.

It is generally believed that amiodarone is a highly effective yet toxic agent. However, the reported long-term effectiveness of amiodarone for recurrent ventricular tachycardia or fibrillation ranges from 28 % and 95 % .5-10 Likewise, the reported frequency and significance of side effects due to amiodarone vary considerably. 5* 7,g-15 It is possible that this wide variability in effectiveness and tolerance can be attributed to differences in patient selection, amiodarone dosing protocols, length of follow-up and/or criteria for efficacy. Nevertheless, guidelines that would allow for the selection of those patients who may derive the greatest benefit from this agent would be helpful but are still controversial. As an example, the role and usefulness of electrophysiologic testing procedures in order to predict the efficacy of amiodarone remains unclear.6~14-18 Consequently, many patients with life-threatening tachycardias are begun on amiodarone therapy without the benefit of objective evidence that the drug will work.

In the present study, 71 patients with drug- refractory recurrent sustained ventricular tachycardia were treated with amiodarone. A subset of these patients underwent control and repeat electrophysiologic studies after amiodarone therapy. The results

From the Departments of Pharmacy Practice, Medicine, Section of Cardiology and Epidemiology-Biometry; the Colleges of Pharmacy and Medicine and School of Public Health, University of Illinois at Chicago.

Received for publication May 21, 1987; accepted Aug. 10, 1987.

Reprint requests: Jerry L. Bauman, Pharm.D., University of Illinois College of Pharmacy, 833 Wood St., Chicago, IL 60612.

1436

of long-term follow-up regarding side effects and effectiveness are presented. Specific variables that could be used in predicting the effectiveness (or ineffectiveness) of amiodarone were analyzed from these results and guidelines that could increase the long-term success of this agent are suggested.

METHODOLOGY

Patient selection. Criteria for inclusion in the present study were: (1) referral to the University of Illinois Hospital for evaluation and treatment of documented recurrent sustained ventricular tachycardia; (2) ineffectiveness or intolerance to conven- tional, approved antiarrhythmic drugs; and (3) informed written consent for amiodarone therapy. Between August, 1979, and July, 1984, 71 patients met these criteria and are the subject of this report.

Patient evaluation. Electrocardiograms (ECGs) were obtained from referring physicians and were reviewed. Ventricular tachycardia was diagnosed by standard criteria and was considered to be sustained if medical intervention including antiarrhythmic drugs, pacing, or direct-current cardioversion was required for termination. The presence or absence of organic heart disease was determined by history, physical examination, echocardiography, radionu- elide ventriculography, treadmill exercise testing and, when clinically indicated, by diagnostic cardiac catheterization. Standard criteria were used to diag- nose and classify organic heart disease.

Patient characteristics (Table I). There were 53 men and 18 women with ages at the time of inclusion into the study ranging from 16 to 77 years (mean +- standard deviation, 58 f 13). Of the 71 patients, 69 had organic heart disease. These 69 patients con- sisted of 54 with ischemic heart disease (48 with documented remote myocardial infarction), 11 with

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Amiodarone - 71 pts I

Long-Term Therapy - 65 pts

Sudden Death - 13 pts No Recurrence - 28 pts

Fig. 1. Algorithm outlining the outcomes of the 71 patients treated with amiodarone for recurrent sustained ventricular tachycardia and of the 65 patients placed on long-term therapy with this agent. Number of patients are shown for each group. VT = ventricular tachycardia; therapy modified = dosage increase or another antiarrhythmic agent added to regimen.

idiopathic dilated cardiomyopathy, three with valvular heart disease (two with mitral valve prolapse and one with aortic stenosis), and one with congenital heart disease (post surgical repair of tetralogy of Fallot). Ejection fractions determined by radionu- elide ventriculography or cardiac catheterization were available in 65 patients and ranged from 8 % to 65% (32 it 15%).

By definition, all 71 patients had a history of documented sustained ventricular tachycardia not associated with an acute myocardial infarction. Of the 71 patients, 11 also had at least one documented episode of ventricular fibrillation. The patients had been unsuccessfully treated (judged by history or electrophysiologic testing) with from two to seven (mean, 4.4 + 1.4) approved and/or investigational antiarrhythmic drugs prior to the amiodarone therapy.

Electrophysiologic studies. All antiarrhythmic drugs were discontinued for at least 5 elimination half-lives prior to control electrophysiologic studies. These studies were completed in the nonsedated state after an informed consent had been obtained. Programmed stimulation was performed from the distal two poles of a quadripolar catheter located at the right ventricular apex and/or the right ventricular outflow tract. Single and double ventricular extrastimuli, delivered at strength approximately twice diastotic threshold, were introduced during ventricular paced rhythm at multiple cycle lengths (400 to 600 msec), followed by bursts (10 to 20 beats) of ventricular stimuli incremented from 120 to 250

Table 1. Patient characteristics

Age Sex Heart disease

Ischemic Cardiomyopathy Valvular Congenital None

Ejection fraction Number of antiarrhythmic drugs

prior to amiodarone

58 + 13 yrs 53 male; 18 female

54 11

3 1 2

32 +- 15% 4.4 f 1.4

bpm. The specific stimulation protocol used in our laboratory for the induction of ventricular tachycardia has been previously reported.1sp20

Induced ventricular tachycardia was considered to be sustained if it persisted for 30 seconds or longer and/or required termination by programmed stimulation or direct-current cardioversion. Ventric- ular tachycardia was nonsustained if only brief episodes (less than 30 seconds), causing no hemody- namic compromise, were induced. Of the 71 patients, 63 had control electrophysiologic studies. In the remaining eight patients, seven had frequent/ incessant ventricular tachycardia so that programmed stimulation was considered unnecessary and in one patient cardiac catheterization was felt to be contraindicated because of severe peripheral vascular disease. Of the 63 patients with control electrophysiologic studies, 52 had inducible sus-

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tained ventricular tachycardia, eight had inducible nonsustained ventricular tachycardia (4 to 48 beats), and the clinical tachycardia could not be replicated by programmed stimulation in three patients.

After control studies, all patients were given 1400 mg of amiodarone every day for 7 days, followed by a maintenance dosage of 400 mg daily. In 36 patients, repeat electrophysiologic studies were performed after 3 weeks of amiodarone therapy (1 week of 1400 mg/day and 2 weeks of 400 mg/day), with the use of a stimulation protocol identical to that used in the control study. Of the 36 patients, 31 had inducible sustained ventricular tachycardia and 5 had inducible nonsustained ventricular tachycardia during control programmed stimulation. The results of the repeat study after 3 weeks of amiodarone were not utilized to guide long-term amiodarone therapy. In these 36 patients, electrophysiologic variables noted during control and repeat studies were scrutinized. Specifically, the change in the rate of induced tachycardia, change in the duration of induced tachycardia, and change in the mode of initiation of the tachycardia were examined. A faster or slower tachycardia was arbitrarily defined as a change in cycle length of the tachycardia of 60 msec or greater compared to control (1 standard deviation of tachycardia rate for the 60 patients with inducible ventricular tachycardia during control programmed stimulation). A significant change in duration of the tachycardia was defined as inducible sustained ventricular tachycardia during control and inducible nonsustained ventricular tachycardia during repeat testing on admiodarone (or vice versa). Ventricular tachycardia that was more easily induced was that requiring a less aggressive mode of the stimulation protocol and ventricular tachycardia that was more difficult to induce was that requiring a more aggressive mode of stimulation. The mode of ventricular stimulation listed in stepwise fashion from least aggressive to most aggressive was as follows: (1) one premature extrastimuli introduced during ventricular pacing; (2) two premature extrastimuli introduced during ventricular pacing; and (3) rapid ventricular burst pacing.

Long-term follow-up. The patients were discharged from the hospital on amiodarone therapy and were followed on an ambulatory basis. These patients were initially seen in the clinic 2 weeks and 1 month after discharge and then at 3-month intervals. The follow-up period extends through March, 1986. The patients were questioned regarding side effects and possible recurrences of symptomatic tachycardia. Recurrences of ventricular tachycardia were documented by continuous ambulatory ECGs (Holter) or

telephonic transmissions of cardiac rhythm (Cardio- beeper, Survival Technology Inc., Bethesda, Md.). For the purposes of this study, sudden death while on amiodarone therapy was defined as death, unat- tributable to pump failure, acute myocardial infarction, or other non-cardiac diseases or events, occurring in a patient who was asymptomatic 24 hours prior to death.

During long-term amiodarone therapy, the follow- ing strategy was pursued. When a symptomatic recurrence of ventricular tachycardia was documented, modification of amiodarone therapy was considered. This modification could entail a dosage increase, addition of another antiarrhythmic agent, or discontinuation of amiodarone and the employ- ment of surgical treatment approaches. Recurrence of ventricular tachycardia within 1 month of initiating amiodarone was generally not considered a drug failure because it was presumed that a pharmacoki- netic steady-state had not yet been obtained. When a patient experienced a side effect that was considered to be intolerable, other treatment alternatives were considered, including dosage reductions or drug discontinuation.

Statistical analysis. Statistical analysis was performed with the chi square test and the Mantel- Haenszel trend test for the comparison of proportions on independent samples and with the Stu- dent’s t test for both paired and unpaired data. All data are expressed as mean & standard deviation. Stepwise logistic regression analysis was used to examine the interplay among electrophysiologic variables that best predicted the patient outcome. Actuarial analysis was performed to control for differences in the length of patient follow-up. Esti- mates from the life table curves are expressed as proportion * standard error. All analyses were made with the SAS statistical package (SAS Insti- tute, Cary, N.C.).

OBSERVATIONS

Efficacy and safety. Fig. 1 shows, in an algorithm form, the outcome of the 71 patients with sustained ventricular tachycardia placed on amiod,arone therapy. Of the 71,6 patients required drug discontinuation prior to discharge from the hospital (less than 1 month after amiodarone was started). Of these six patients, four (6% ) patients had worsening of underlying ventricular tachycardia on amiodarone, one patient had torsade de pointes,, and one patient had severe vasculitis. The remaining 65 patients were started on long-term amiodarone therapy and were followed for 1 to 74 (22 + 17) months. Of these 65 patients, an additional 3 patients required the

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A I

6

I

i *o-

g lo-

I I I 1 1 I 1 1 10 20 30 40 50 60 70 60

TIME (MONTHS)

Fig. 2. Actuarial analysis of patients receiving amiodarone for recurrent sustained ventricular tachycardia. Curve A represents percent of patients successfully receiving amiodarone, including those with a documented recurrence and resultant therapy modification. Curve B represents percent of patients successfully receiving amiodarone without a documented symptomatic recurrence of ventricular tachycardia or side effects that required discontinuation of therapy. The vertical bars represent standard error.

discontinuation of amiodarone due to side effects- two with pulmonary fibrosis (diagnosed at 16 and 13 months of therapy) and one with torsade de pointes (at 4 months of therapy). Thirteen patients suffered sudden death while receiving amiodarone therapy after 1 to 19 (9 f 7) months of therapy. Of the 65 patients on long-term amiodarone, 21 had a symptomatic recurrence of ventricular tachycardia; amiodarone was discontinued in six of these patients after 2 to 17 (6 + 5) months of therapy. In the remaining 15 patients with recurrence of ventricular tachycardia, amiodarone was continued. In seven of these patients another antiarrhythmic drug was added to the regimen; in five patients the dosage of amiodarone was increased to 600 mg/day and in three patients therapy was not modified because it was felt that the frequency and symptoms of the tachycardia had been significantly improved. The subsequent follow-up in these 15 patients since the time of initial recurrence was 0.5 to 72 (20 + 20) months. Of the original 71 patients, 28 (39%) are taking amiodarone, 400 mg/day alone, for 5 to 55 (29 f 15) months without recurrence of symptomatic ventricular tachycardia.

Fig. 2 presents the life table curves for the 71 patients treated with amiodarone, showing both those patients who received a modified amiodarone regimen (dosage increased or another agent added) and those whose regimen remained unchanged. By actuarial analysis, it was estimated that 57 -t 6% of patients will be able to continue amiodarone (either

Table Il. Side effects of amiodarone-71 patients*

Hepatic (elevated liver enzymes) 28 Neurologic (paresthesias, sleep 21

disorders, ataxia) Dermatologic (photosensitivity, 13

blue-grey color) Gastrointestinal (anorexia nausea, 13

constipation) Hypothyroidism

Low T, only 5 Clinical symptoms and low T, 9

Cardiac Symptomatic bradycardia 8 Arrhythmia aggravation 5t Torsade de pointes 2

Pulmonary 4 Visual (blurred vision) 3

* Most common side effects in each category are listed in parentheses. tone patient developed incessant ventricular tachycardia that responded to the addition of procainamide; in this case amiodarone was not discontinued.

alone or with a modified regimen) for 24 months. Further, it was estimated that 36 ? 7% of patients will have long-term prevention of ventricular tachycardia without intolerable adverse effects while taking amiodarone, 400 mg/day alone, for 24 months.

Side effects, including suspected arrhythmia aggravation and drug-related torsade de pointes, were documented in 58 (82%) of the original 71 patients and in 52 (80%) of the 65 patients placed on long-term amiodarone therapy. The follow-up in

1440 Bauman et al.

Table III. Electrophysiologic variables-32 patients

Failure + Success

Mode of VT induction Easier 8 3 Harder 1 5 Same 9 6

VT duration? Longer 1 3 Shorter 2 1 Same 15 10

VT rate Faster 3 5 Slower 9 7 Same 6 2

VT = ventricular tachycardia. *Recurrence of VT or sudden death. iLonger duration denotes change from nonsustained VT (control) to sustained VT (amiodarone); shorter duration denotes change from sustained VT (control) to nonsustained VT (amiodarone).

those patients who had side effects due to long-term amiodarone was 26 A 17 months compared to 9 + 7 months for those patients who had no side effects documented (p < 0.001). These side effects are grouped in broad categories and are listed in Table II. Of the 71 patients, side effects severe enough to warrant the discontinuation of amiodarone occurred in nine patients (13%). These side effects were suspected arrhythmia aggravation in six patients (including two with torsade de point+ pulmonary fibrosis in two patients, and vasculitis in one patient. Despite discontinuation of amiodarone, one patient died due to drug-related pulmonary fibrosis. No other patients died due to amiodarone toxicity. Side effects that necessitated a dosage reduction (to 200 mg/day) occurred in five patients. The specific side effects in these five patients were suspected pulmonary toxicity in two patients, suspected hepatotoxic- ity in one patient, ataxia and anorexia in one patient, and peripheral neuropathy in one patient.

Factors influencing long-term outcome. Of the 71 patients, 36 had repeat electrophysiologic studies while receiving amiodarone therapy. In these 36 patients, induced ventricular tachycardia after amiodarone therapy was sustained in 27, nonsustained in 5, and the tachycardia could not be induced in the remaining 4. The mean cycle length of the induced tachycardia was 345 -+ 54 msec while these patients were receiving amiodarone therapy compared to 301 + 62 msec during the control study @ < 0.01).

The proportion of patients receiving long-term amiodarone (400 mg/day) with symptomatic recurrence of ventricular tachycardia or sudden death was compared to the proportion of patients without

a recurrence of their tachycardia with respect to several variables noted during control and repeat electrophysiologic studies: (1) rate of induced tachycardia; (2) duration of induced tachycardia; and (3) mode of tachycardia induction (Table III). There was no significant difference in the proportions of those with and without arrhythmia recurrence or sudden death when a faster or slower rate of the tachycardia was induced. Induction of sustained ventricular tachycardia during control and nonsustained ventricular tachycardia while the patients were receiving amiodarone therapy (or vice versa) also had no influence on the recurrence rate of the arrhythmia. However, when the mode of ventricular tachycardia induction was examined, 8 of 11 (73%) patients with a more easily induced tachycardia while they were receiving amiodarone had arrhythmia recurrence or sudden death, and 9 of 15 (60 % ) with the same mode of induction had recurrence or sudden death, while only one of six (17 % ) of the patients with a more difficult tachycardia induction experienced arrhythmia recurrence or suffered sudden death (p < 0.05). Of the four patients in whom the tachycardia could not be replicated during programmed stimulation with amiodarone, two have been free of arrhythmia recurrence after 26 and 64 months of therapy, one died suddenly after 11 months of therapy, and one had recurrence of ventricular tachycardia after 3 months of therapy.

Since this series of comparisons does not examine the influence of the combination of the above variables, a stepwise logistic regression analysis was performed. The three variables noted during electrophysiologic testing of amiodarone (tachycardia rate, duration, and mode of induction), along with ejection fraction (less than or greater than 40% ), were evaluated by this procedure. The only variable that entered the regression as a significant predictor of recurrence of ventricular tachycardia or sudden death was mode of tachycardia induction (p < 0.025). The odds ratio estimate for a more easily induced tachycardia vs a tachycardia that was more difficult to induce was 22.1, with 95% confi- dence intervals (1.6, 302.3). No other variables or combinations of variables were significant in predicting which patients would have successful long- term therapy. In other words, a more easily induced tachycardia while the patient was taking amiodarone (compared to the control study) suggested that arrhythmia recurrence or sudden death would occur during long-term therapy, and a tachycardia that was more difficult to induce while the patient was taking amiodarone suggested that long-term therapy would be successful in preventing recurrences of

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ventricular tachycardia or sudden death. For patients with the same mode of induction during control studies and amiodarone testing, there were no other variables that could be useful in predicting long-term success or ineffectiveness. Although ejection fraction was not helpful in predicting which patients had arrhythmia recurrence, the relation- ship of ventricular function and sudden death was analyzed. Of the 42 patients with ejection fractions less than 40%) 12 (29%) died suddenly compared to 1 of the 22 (4%) patients with ejection fractions greater than 40% (p < 0.05).

The significance of an early recurrence (less than 1 month of amiodarone therapy) of sustained ventricular tachycardia was also examined. Of the 65 patients discharged and receiving amiodarone therapy, 11 of 15 (73%) with early recurrence also had arrhythmia recurrence or sudden death during long- term therapy, whereas 23 of 50 (46%) without early recurrence had arrhythmia recurrence or sudden death during long-term therapy 0, < 0.01).

COMMENTS

It has recently been stated that amiodarone is a “beguiling but frustrating drug.“21 Although amiodarone is generally perceived to be both highly effective and toxic when administered to patients with drug-refractory tachycardias, the reported long-term success rate varies considerably?lo

Long-term efficacy and safety. In the present study, the actuarial success rate for amiodarone alone (without a dosage increase or the addition of another antiarrhythmic agent because of tachycardia recurrence) was estimated to be 36 + 7% after 2 years of therapy. This is somewhat similar to the 28 + 9% actuarial success rate found by Fogoros et al5 It is important to note that those studies that analyzed the long-term success of amiodarone by the use of life table analysis generally showed a significantly lower percentage of patients that were able to remain on amiodarone than did studies that did not employ those methods. Actuarial analysis controls for differences in the length of patient follow-up and loss of follow-up, which probably provides for a more realistic estimate of long-term success rate.22 Another factor that may help to explain the wide variability in the reported long-term effectiveness of amiodarone may be differences in patients selection; perhaps those studies with lower success rates included more patients who were “drug refractory” to a greater extent than the reports with higher success rates.

The long-term success rate of amiodarone does not seem any better than that observed for other

approved and investigational antiarrhythmic drugs. For example, we have previously estimated2 that disopyramide will be both tolerated and effective in 54 f 10% of patients after 24 months of therapy. However, it is important to point out that this is not a fair comparison for two reasons. First, amiodarone is usually administered to patients who have failed to respond to a plethora of agents and who are therefore drug-refractory to a greater extent. Sec- ond, in the present study, amiodarone was administered to patients without the advantage of objective evidence that it would be effective, whereas selection of other agents, such as disopyramide, is generally guided by electrophysiologic drug testing.

This study shows a side effect profile for long- term amiodarone therapy that is similar to that found in other reports. 5*7,s-13 However, a greater overall percentage (about 80%) of our patients suffered from amiodarone-related toxicity than has been previously described. Since many of the significant side effects due to amiodarone occur during chronic administration, the most likely explanation for this finding is that the follow-up period in our population is somewhat longer than that in previous work. In fact, those few patients in our trial who have not had side effects due to amiodarone have had significantly shorter follow-up periods than those patients in whom side effects were observed. It is quite possible that the patients without side effects at the present time will experience toxicity as the duration of therapy increases. Despite the high incidence of side effects observed in this trial, only 3 of the 65 (5%) patients who were receiving long- term therapy required drug discontinuation due to these side effects. This finding probably reflects the rather limited therapeutic alternatives available in these patients. In other words, patients are more likely to tolerate drug toxicity and continue therapy if alternative therapy is not available or is unattrac- tive.

Role of repeat electrophysiologic studies. It is obvi- ous that the availability of objective criteria that may predict the long-term effectiveness or ineffectiveness of amiodarone would be clinically valuable. The present study evaluated variables noted during electrophysiologic studies (rate, duration, and mode of induction of ventricular tachycardia) and an index of left ventricular function (ejection fraction). The only variable that was significant in this regard was the mode of tachycardia induction; a group of patients with a more easily induced tachycardia while taking amiodarone, compared to the control study, tended to have recurrence of ventricular tachycardia or sudden death, and a group of patients

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with a tachycardia that was more difficult to induce tended to have successful long-term therapy. We were cautious in interpreting the significance of this potentially important finding for several reasons. First, the number of patients with ventricular tachycardia induced while they were taking amiodarone by either a less aggressive or by a more aggressive stimulation protocol was relatively small. Second, a lack of reproducibility in the induction of ventricular tachycardia has recently been reported.23 For these reasons, we examined the only two other studies that analyzed the mode of tachycardia induction in patients who were taking amiodarone. McGovern et alz4 found that 10 of 18 (56 % ) patients with the same or a more easily induced tachycardia while taking amiodarone had recurrence of ventricular tachycardia or sudden death, whereas none of the five patients with a tachycardia induced by a more aggressive stimulation protocol had recurrence or sudden death. These investigators did not separate those patients with the same or with a less aggressive mode of stimulation. Naccarelli et alz6 found that 9 of 13 (69%) patients with a more easily induced tachycardia while taking amiodarone had symptomatic recurrence, compared to one of six (17%) patients with a tachycardia that was more difficult to induce. Thus, these two studies report findings very similar to those presented in this study. Although combining data from several different institutions and populations has possible hazards, the types of patients and stimulation protocols of these two studies are also similar to those in the present investigation. Adding our data to that reported in the studies by McGovern et al. and by Naccarelli et al. shows that 40 of 74 (54%) patients with tachycardia that was induced with a less aggressive or identical mode of stimulation during amiodarone treatment had recurrence of ventricular tachycardia or sudden death. In contrast, only 2 of 17 (12%) patients with a tachycardia that was more difficult to induce had arrhythmia recurrence or sudden death (p < 0.001).

Therefore, we believe it is clear that a change in the mode of induction is useful in predicting which patients will respond adequately to long-term amiodarone therapy. Moreover, repeat electrophysiologic studies with patients taking amiodarone can be beneficial in making clinical decisions regarding the treatment of refractory ventricular tachycardia. Thus, one should consider therapy modifications in patients taking amiodarone who have a more easily induced tachycardia (e.g., increase in dosage or addition of another ant&rhythmic agent). Two problems remain. The usefulness of mode of induc-

tion is not universal, after amiodarone therapy, occasional patients with a tachycardia that is more difficult to induce will have a recurrence of ventricular tachycardia. Also, since we were unable to discern useful predictors in patients who have the same mode of induction during the control study and while receiving amiodarone therapy, it is difficult to make clinical decisions based upon programmed stimulation in these individuals at the present time. Although a change in the rate of the induced ventricular tachycardia during repeat testing does not seem to influence the chance of recurrence, it may predict subsequent symptomatology and the risk of sudden death. In a recent study by Horowitz et al.,17 50% of patients with severe symptoms during induced ventricular tachycardia died suddenly, compared to none of the patients who were able to tolerate their rhythm after amiodarone loading, despite nonfatal recurrences. The rate of induced ventricular tachycardia was significantly faster in those patients with severe symptoms. The authors suggest that a long-term trial with amiodarone can be considered in patients with a slow, well-tolerated ventricular tachycardia induced after amiodarone, but other therapy should be attempted in patients with a fast, symptomatic rhythm. Our study did not contain a sufficient number of patients to allow a separate analysis of the effect of change in rate on the incidence of sudden death (without symptomatic recurrence).

Other factors influencing outcome. Several other findings require further discussion. Although ejection fraction was not useful in determining the long-term success of amiodarone, patients with an ejection fraction of less than 40% were more likely to die suddenly than patients with better ventricular function. The explanation of this observation remains unclear. One possibility is that, if ventricular tachycardia recurs in a patient with severe ventricular dysfunction, it often results in a fatal outcome, whereas patients with relatively good ventricular function will more often survive a recurrence of their arrhythmia.

Additionally, patients with an early recurrence of ventricular tachycardia (less than 1 month of amiodarone therapy) tended to also have recurrence or sudden death with long-term therapy. We usually ignored an early recurrence of ventricular tachycardia in these patients, unless proarrhythmic actions were suspected, because it was presumed that steady-state had not yet been achieved and therefore the recurrence did not accurately reflect the possibility of long-term success. However, early recurrence may serve to identify those patients with

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a worse or more frequent ventricular tachycardia that will often not respond to long-term amiodarone therapy once steady-state and a full therapeutic effect is achieved.

In conclusion, amiodarone is a useful agent for the treatment of drug-refractory recurrent ventricular tachycardia, although it is obviously not the ideal antiarrhythmic drug. About one half of patients are able to remain on amiodarone for 2 years, although some patients. require dosage modification or the addition of other antiarrhythmic agents. Further, a large percentage of patients will experience a wide spectrum of side effects due to amiodarone. Repeat electrophysiologic studies with patients taking amiodarone are useful in guiding long-term therapy, particularly if one scrutinizes the change in the mode of induction. Additional research is necessary in order to further refine this and other predictive variables that may be helpful in the care of these patients.

SUMMARY

The reported long-term efficacy and safety of amiodarone varies considerably. Further, the role of electrophysiologic drug testing of amiodarone theia- py is controversial, In this study, 71 patients with drug-refractory, recurrent sustained ventricular tachycardia were treated with amiodarone and were followed over 20 + 17 months. Amiodarone had to be discontinued prior to discharge in 6 of the 71 patients because of suspected proarrhythmic actions or side effects Of the remaining 65 patients started on long-term amiodarone, 21 (32%) had recurrence of ventricular tachycardia and 13 (20%) died suddenly. Of the 21 patients with recurrence of ventricular tachycardia while receiving amiodarone, 15 remained on amiodarone, with or without a therapy modification; the remaining six required drug discontinuation By actuarial analysis, 57 + 6% of patients will be able to continue amiodarone, with or without a therapy modification for 2 years and 36 t- 7% will have successful long-term therapy without a recurrence of VT or intolerable side effects for 2 years. Of 63 patients with control electrophysiologic studies, 36 had repeat programmed stimulation after 3 weeks of amiodarone therapy. By chi square and logistic regression analyses, the mode of induction of ventricular tachycardia with amiodarone was useful in predicting long-term outcome. Patients with a more easily induced ventricular tachycardia after amiodarone (compared to control studies) were at higher risk of ventricular tachycardia recurrence or sudden death, whereas patients with a ventricular tachycardia that was

Long-term amiodarone therapy 1443

more difficult to induce tended to have successful long-term therapy.

In summary, a subset of patients with drug- refractory ventricular tachycardia can be successfully treated with amiodarone although therapy modifications are often required. The mode of ventricular tachycardia induction with amiodarone therapy may be helpful in predicting which patients are more likely to have successful long-term therapy and which patients may require therapy modification or other treatments. Repeat electrophysiologic studies after several weeks of amiodarone therapy can be useful in guiding therapy decisions in patients with recurrent ventricular tachycardia.

The authors would like to thank all past cardiology attending physicians for their contribution to the care of these patients and Dr. Steven Swiryn and the late Dr. Kenneth Rosen for their guidance in initiating this project. The technical assistance of Darryl Prechel is appreciated.

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Amiodarone for sustained ventricular tachycardia: Efficacy, safety, and factors influencing...

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