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Evaluation of antiarrhythmic efficacy of amiodarone in VT
FORUM-LETTERS
ANGlOGRAPHIC EVALUATION CARDIOMYOPATHY
TO THE EDITOR
OF HYPERTROPHIC
To the Editor: In their recent article in the
REPLY To the Editor: Dr. Valles is correct in his assertion that nonangled ventriculography is adequate in evaluating most patients with HCM. In our view, however, the important question is not what suffices in most patients but what is optimal in all patients. When two techniques (or in this case, views) are available we believe the one which goes farthest toward complete evaluation should be used unless there are overwhelming technical or clinical reasons to do otherwise. An analogous situation exists in coronary angiography. We suspect that in most patients, two views of each coronary artery would uncover most lesions. Clearly this is unacceptable and so additional views are done unless the patient is extremely unstable. Each additional view has less of a statistical probability of adding new information than its predecessors, but the final result is a complete study which misses few if any lesions. In the evaluation of HCM, the purpose of angiocardiography is not to merely duplicate information which is readily obtained by echocardiography (e.g., SAM), but rather to exclude pathology which is not identifiable by other means. This is where axial and angiography (in this case the cranial LAO view) is superior to nonangled views, and except for the patient too large to penetrate radiographically, we know of no good reason not to use the cranial view. It is our opinion that the value of axial angiography is sufficiently established in adult and pediatric angiography to warrant routine performance. It will not make a difference in
every patient, demonstrates
but will this well.
in
many.
Case
No.
3 in
our
report
Curtis Larry
E. Green, M. D. P. Elliott, M. D. Dept. of Radiology Georgetown University Hospital 3800 Reservoir Road, N. W. Washington, DC 20007
EVALUATION OF ANTIARRHYTHMIC OF AMIODARONE IN VT
EFFICACY
To the Editor: We read with interest the report of Nademanee et al.’ on the efficacy of amiodarone in ventricular arrhythmias. The report emphasized symptomatic improvement in all 13 patients despite inducible sustained or nonsustained ventricular tachycardia (VT) in four patients. They recorded 95% to 98? suppression of spontaneous ventricular ectopic activity on amiodarone for this group of patients, and have implied that this is a better predictor of amiodarone efficacy than programmed electrical stimulation (PES). This conclusion, as the authors rightly emphasize, is in direct contrast to observations with type I antiarrhythmic agents. We have examined this question further on the basis of our own previously reported studies’,) as well as that reported in this article1 and offer the following observations. We note that in the group of Nademanee et al. there was almost equal division between patients with sustained and nonsustained ventricular tachycardia. Two of the latter group had no known heart disease. The prognosis of nonsustained ventricular tachycardia may not necessarily parallel that of sustained ventricular tachycardia.’ The clinical significance of induced nonsustained ventricular tachycardia during programmed electrical stimulation remains controversial. At the present time it may be desirable to separate these two groups of patients for prognostic analysis. The relationships between exact timing of the follow-up electrophysiologic studies and serum amiodarone levels as well as the relationship of both to prior drug dose is unclear. We observed that two of the three patients with inducible sustained ventricular tachycardia were studied after only 2 weeks of therapy. The authors used clinical symptoms as an end point, though serial Holter monitoring was performed. We recently reported on the chronic electrophysiologic, systemic, and pharmacologic effects of amiodarone’ in a homogenous group of 17 patients with sustained ventricular tachycardia and organic heart disease. In reviewing the changes in the electrocardiographic and electrophysiologic parameters reported by us as compared to the present report,’ we observed a considerably wider spectrum of effects. Specifically, we noted additional significant increases in QRS duration, corrected sinus node recovery time, ant1 HV intervals. The latter has been confirmed by other investigatorsJ We are of the opinion that amiodarone has depressant electrophysiologic effects on all electrically active cardiac tissue. Its effects on sinus node function, while originally ascribed to its adrenergic antagonist effects, may indeed be related to primary changes in automaticity.6 This would of necessity question its status as a pure type III antiarrhythmic agent. In our series of patients, we have not observed the degree of suppression of ventricular ectopic activity reported in this article.’ Only one patient continues to have single premature ventricular depolarizations, while the remainder continue to have 165
166
Letters
to the Editor
CHRONIC
rapid
EPS
LV pacing
bolter
VT
on
Table
ON AMIOOARONE
cl 484
NSR
ms
amiodarone
I. Sustained
VT
Spontaneous Control Completion of maintenance phase Recurrence of VT (1 mo-I
Inducible ut PES
17
16
iJ
7
4
(4)*
Ambulatory ECG
Exercise ECG
Not performed 1
Not performed 2
(a*
(a*
yr) *Numbers
in parentheses
During
v’xerciit
Iking
Holtt,~
prediction
: I ml11
of amiodarone
response
.it !
100
:2 ;
I ! IO ’ r
>
12 month:
Fig. 1. Induction of VT by electrophysiologic study (EPS) during amiodarone therapy (top panel). Holter monitor performed 1 year later on continued amiodarone therapy shows episodes of slow spontaneously terminating VT (see text).
Table
II. Prospective
indicate
detection
of recurrent
VT by each
technique. complex ventricular ectopic activity. The doses employed and the serum amiodarone levels obtained on chronic therapy in these patients have been in the therapeutic range. In examining the data of Nademanee et al., we have noted that patients No. 2, 5, and 7 did not meet their criteria of 95”U suppression. While we, too, have been impressed by amiodarone’s efficacy in suppressing ventricular ectopic activity as compared to other agents, the degree of success reported herein! is not what we have routinely seen in our experience. Table I summarizes our experience with induction of sustained ventricular tachycardia during chronic electrophysiologic studies. These studies were performed a mean of 32 days after initiation of amiodarone therapy. Amiodarone was administered in a multiple dose schedule in these patients. As can be noted, 7 of 16 patients who had inducible sustained ventricular tachycardia during control electrophysiologic studies were reinducible during the chronic study. However, in a follow-up ranging from 70 to 457 days, four of the seven patients with inducible sustained ventricular tachycardia have had recurrences. In all instances these patients were not hemodynamically compromised during the recurrence, with the arrhythmia being significantly slowed. Fig. 1 illustrates induction of ventricular tachycardia in such a patient during chronic electrophysiologic studies. The ventricular tachycardia is slow and spontaneously terminating. This patient had
almost comp1et.e abolition of ventricular ectopic activity, but Holter monitor performed 1 year later shows episodes of slow spontaneously terminating ventricular tachycardia. in our studies, continuous 24-hour ambulatory monitoring was performed from the initiation of amiodarone therapy until chronic electrophysiologic studies. Serial monitoring was performed at Z&month intervals subsequently. We believe that this intensive monitoring protocol has resulted in the detection of minimally symptomatic and infrequent ventricular tachycardia in our patients. However, we have observed acceleration of this ventricular tachycardia during exercise in the same patient. In cornpar.. ing programmed electrical stimulation performed after 1 month of amiodarone therapy to Holter monit.oring and exercise testing at the same intervals, it is apparent that programmed electrical stimulation is more sensitive and moderately specific (Table 11). Authors reporting on amiodarone have emphasized the discordance between programmed electrical stimulation studies and subsequent clinical results. We consider the limitations of subsequent clinical detection of minimally symptomatic arrhythmias to be an important variable. In reviewing similar data from other studies,
we noted
~4 much
higher
incidence
of recurrent
symptom
atic ventricular tnchycardia in patients who remained inducible on amiodarone therapy.‘,” We think t.hat the difference in arrhythmia recurrence in patients who remain noninducible during chronic electrophysiologic studies as compared to those who do remain inducible may be significant. The limited follow. up and the small number of patients In all our studies preclude a conclusive statement in this regard. We support (;raboys editorial plea for “numerators in search of denominators” an applied t.o programmed eleckrical stimulation studies.” 111 t;jct. studies on :he clinical sensitivity and specificity of programmed electrical stimulation protocols are sorely needed. We ha\fe recently reported that stimulation techniques influence bot,h the cycle length and the morphology of the induced arrhythmia. This is particularly true when complex and aggressive stimulatiun techniques are applied.‘” While the earlier studies utilized comparatively simpler techniques of single and double extrastirnulr and rapid pacing, the specificity of those studies appears 1~ he higher than present techniques that 11se multiple extrastimuli and high-rate ventricular pacing. These induced arrhythmias in the clinical electrophysiology laboratory are frequently hrmodynamically and electrically more unstable than the patient.‘> spontaneous arrhythmia, exposing the patient to a greater need for pharmacologic or electrical termination of the arrhythmia. Wr believe that the question of the sensitivity and specificity of programmed electrical stimulation techniques is important enough to warrant a multicenter cooperative approach for examination of this problem. .Snnjeev Saksena, M.D Stephen 7’. Rothbart. M.1). Gail Cappeilo. R.N. ( ‘urdiac Electrophysiology
Volume
105
Number
1
REFERENCES 1. Nademanee K, Hendrickson J, Kannan R, Singh BN: Antiarrhythmic efficacy and electrophysiologic actions of amiodarone in patients with life-threatening ventricular arrhythof spontaneously-occurring mias: Potent suppression tachyarrhythmias versus inconstant abolition of induced ventricular tachycardia. AM HEART J 103:950, 1982. 2. Saksena S, Rothbart ST, Kaufmann WE, Rathyen W: Chronic electrophysiologic, systemic and pharmacologic effects of amiodarone in recurrent ventricular tachycardia. Am J Cardiol 49:1044, 1982. 3. Saksena S, Rothbart S, Kaufmann WE: Amiodarone in ventricular tachycardia. N Engl J Med 26:1587, 1981. 4. Follansbee WP, Michelson EL, Morganroth J: Nonsustained ventricular tachycardia in ambulatory patients: Characteristics and association with sudden cardiac death. Ann Intern Med 92:741, 1980. 5. Gloor HO, Urthaler F, James TN: The immediate electrophysiologic effects of amiodarone on the canine sinus node and AV junctional region. Am J Cardiol 49:981, 1982. 6. Akhtar M. Shenasa M. Denker S. Gilbert C: Electronhvsiologic effect of amiodarone on His Purkinje conductibn*and refractoriness in man. Clin Res 30:167A, 1982. EN, Jackman WM, Naccarelli GW, 7. Heger JJ, Prystowsky 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 305:539, 1981. 8. Morady F, Scheinman M, Hess D: Amiodarone in the management of patients with malignant ventricular arrhythmias. Circulation 64:IV-36, 1981. 9. Graboys TB: The stampede to stimulation-numerators and denominators revisited relative to electrophysiologic study of ventricular arrhythmias. AM HEART J 103:1089, 1982. 10. Saksena S: Limitations of current techniques for induction of ventricular tachycardia. Clin Res 29:659A, 1981.
REPLY To the Editor: We appreciate the opportunity to respond to Dr. Saksena and his colleagues about their comments on our data on amiodarone in the treatment of life-threatening ventricular tachyarrhythmias, recently published in the JOURNAL.’ The authors raise numerous issues based on their essentially unpublished data from a relatively small number of patients, apparently studied without a stringent protocol and, as the authors themselves indicate, followed for a limited duration of time. Their main contention appears to be that electrophysiologic testing is a more sensitive and reliable technique than serial Holter monitoring in gauging the long-term efficacy of amiodarone; this is an issue that is of crucial therapeutic importance. Unfortunately, the data on which the authors base what are clearly tentative conclusions are very limited and fragmentary. For example, as is evident in their Table I, 24.hour Holter monitoring was carried out (to serve as a control recording) in none of their patients before the initiation of amiodarone therapy. Thus a change effected by the drug intervention short-term or long-term cannot be judged meaningfully. Furthermore, Dr. Saksena and associates emphasize the limitations of the clinical detection of minimally symptomatic arrhythmias as a variable that might explain the observed discrepancy between their data and ours. They attempted to overcome this difficulty (as we did also) by intensive regular Holter monitoring during chronic therapy. However, they do not indicate whether they adjusted amiodarone dosage upwards in those patients in whom they found recurrences of symptomatic or nonsymptomatic ventricular tachyarrhythmias. Failure to do this may possibly
Letters
to the Editor
167
lead one to unjustifiably conclude lack of effectiveness on a given dosage regimen of amiodarone. Adjustment of dosage during chronic therapy is necessitated by the variable nature of the pharmacokinetic properties in different patients.* Dr. Saksena and his colleagues state that “The doses employed and the serum amiodarone levels obtained on chronic therapy in these patients have been in the therapeutic range.” However, they do not indicate what constituted their “therapeutic range” of serum amiodarone concentrations, nor do they suggest how the range of concentrations deemed “therapeutic” was established: Was it the range that was effective in preventing inducible ventricular tachycardia (VT), or that which suppressed symptomatic VT, or was it the one that produced premature ventricular contraction (PVC) suppression of a defined degree? We believe that at present the clinical utility of serum amiodarone level measurements is far from being established. For this reason, adequate which is a function of dose as well as “amiodaronization,” duration of therapy, must be judged on an individual basis since the elimination half-life of the drug is exceedingly variable, perhaps between 15 and 65 days.’ Satisfactory dosage regimes may, however, be developed on the basis of indirect parameter? relative to the attainment of predetermined goals of therapy and the development of side effects. Our experience with this approach now extends to over 250 cases of cardiac arrhythmias resistant to conventional antiarrhythmic agents. Recently we have analyzed our data from our first 96 patients with life-threatening ventricular arrhythmias given amiodarone and followed for a mean period of 15 months (range 6 to 40). In 72 patients, 24-hour Holter recordings have been done before as well as serially during chronic therapy; in 43 such patients, arrhythmia induction by programmed electrical stimulation (PES) was undertaken before as well as after adequate “amiodaronization.” The details are being presented elsewhere,’ but in essence the data extend and confirm those that we’,” and others6 have reported in smaller series of patients. It is clear that when amiodarone is used as a single agent in an appropriate dosage regimen, it predictably eliminates the recurrences of symptomatic and nonsymptomatic VT (previously resistant to conventional therapy) in 80r, to 90”; of patients with life-threatening ventricular arrhythmias; such an effect in our experience is accompanied by P 9O’c suppression of total PVCs on Holter recordings. On the other hand, in up to 50°C of such patients (compared to 7 of 16 patients in Dr. Saksena’s series), VT (sustained as well as unsustained) is inducible by PES. As has been noted by others also,’ we have not !seen significant differences between the clinical course of patients in whom tachycardia was inducible on amiodarone and in whom it was not. As indicated by Dr. Saksena, it is conceivable that minor differences (which will require extremely large numbers of patients to demonstrate) between the subsets of patients in whom inducible VT is sustained and in those in whom it is unsustained on amiodarone may be found. However, such differences, if they exist in the case of amiodarone, are unlikely to be of more than theoretical interest as the drug is clinically effective in the largest numbers of patients to whom it is given. As Dr. Saksena and his associates also confirm, even in patients with inducible sustained VT recurrences of spontaneous VT were not associated with hemodynamic compromise, the arrhythmias being slower and :,elf-terminating. In our experience, the arrhythmia may respond to a slightly higher dose or duration of therapy and is rarely associated with fatality. We are, however, intrigued by Dr. Saksena et al’s observation that in all seven of their patients who had inducible VT, the arrhythmia was sustained. Also surprising is their comment that unlike our findings, they discovered “considerably wider spectrum of effects” induced by amiodarone with respect to electro-
ANGlOGRAPHIC EVALUATION CARDIOMYOPATHY
TO THE EDITOR
OF HYPERTROPHIC
To the Editor: In their recent article in the
REPLY To the Editor: Dr. Valles is correct in his assertion that nonangled ventriculography is adequate in evaluating most patients with HCM. In our view, however, the important question is not what suffices in most patients but what is optimal in all patients. When two techniques (or in this case, views) are available we believe the one which goes farthest toward complete evaluation should be used unless there are overwhelming technical or clinical reasons to do otherwise. An analogous situation exists in coronary angiography. We suspect that in most patients, two views of each coronary artery would uncover most lesions. Clearly this is unacceptable and so additional views are done unless the patient is extremely unstable. Each additional view has less of a statistical probability of adding new information than its predecessors, but the final result is a complete study which misses few if any lesions. In the evaluation of HCM, the purpose of angiocardiography is not to merely duplicate information which is readily obtained by echocardiography (e.g., SAM), but rather to exclude pathology which is not identifiable by other means. This is where axial and angiography (in this case the cranial LAO view) is superior to nonangled views, and except for the patient too large to penetrate radiographically, we know of no good reason not to use the cranial view. It is our opinion that the value of axial angiography is sufficiently established in adult and pediatric angiography to warrant routine performance. It will not make a difference in
every patient, demonstrates
but will this well.
in
many.
Case
No.
3 in
our
report
Curtis Larry
E. Green, M. D. P. Elliott, M. D. Dept. of Radiology Georgetown University Hospital 3800 Reservoir Road, N. W. Washington, DC 20007
EVALUATION OF ANTIARRHYTHMIC OF AMIODARONE IN VT
EFFICACY
To the Editor: We read with interest the report of Nademanee et al.’ on the efficacy of amiodarone in ventricular arrhythmias. The report emphasized symptomatic improvement in all 13 patients despite inducible sustained or nonsustained ventricular tachycardia (VT) in four patients. They recorded 95% to 98? suppression of spontaneous ventricular ectopic activity on amiodarone for this group of patients, and have implied that this is a better predictor of amiodarone efficacy than programmed electrical stimulation (PES). This conclusion, as the authors rightly emphasize, is in direct contrast to observations with type I antiarrhythmic agents. We have examined this question further on the basis of our own previously reported studies’,) as well as that reported in this article1 and offer the following observations. We note that in the group of Nademanee et al. there was almost equal division between patients with sustained and nonsustained ventricular tachycardia. Two of the latter group had no known heart disease. The prognosis of nonsustained ventricular tachycardia may not necessarily parallel that of sustained ventricular tachycardia.’ The clinical significance of induced nonsustained ventricular tachycardia during programmed electrical stimulation remains controversial. At the present time it may be desirable to separate these two groups of patients for prognostic analysis. The relationships between exact timing of the follow-up electrophysiologic studies and serum amiodarone levels as well as the relationship of both to prior drug dose is unclear. We observed that two of the three patients with inducible sustained ventricular tachycardia were studied after only 2 weeks of therapy. The authors used clinical symptoms as an end point, though serial Holter monitoring was performed. We recently reported on the chronic electrophysiologic, systemic, and pharmacologic effects of amiodarone’ in a homogenous group of 17 patients with sustained ventricular tachycardia and organic heart disease. In reviewing the changes in the electrocardiographic and electrophysiologic parameters reported by us as compared to the present report,’ we observed a considerably wider spectrum of effects. Specifically, we noted additional significant increases in QRS duration, corrected sinus node recovery time, ant1 HV intervals. The latter has been confirmed by other investigatorsJ We are of the opinion that amiodarone has depressant electrophysiologic effects on all electrically active cardiac tissue. Its effects on sinus node function, while originally ascribed to its adrenergic antagonist effects, may indeed be related to primary changes in automaticity.6 This would of necessity question its status as a pure type III antiarrhythmic agent. In our series of patients, we have not observed the degree of suppression of ventricular ectopic activity reported in this article.’ Only one patient continues to have single premature ventricular depolarizations, while the remainder continue to have 165
166
Letters
to the Editor
CHRONIC
rapid
EPS
LV pacing
bolter
VT
on
Table
ON AMIOOARONE
cl 484
NSR
ms
amiodarone
I. Sustained
VT
Spontaneous Control Completion of maintenance phase Recurrence of VT (1 mo-I
Inducible ut PES
17
16
iJ
7
4
(4)*
Ambulatory ECG
Exercise ECG
Not performed 1
Not performed 2
(a*
(a*
yr) *Numbers
in parentheses
During
v’xerciit
Iking
Holtt,~
prediction
: I ml11
of amiodarone
response
.it !
100
:2 ;
I ! IO ’ r
>
12 month:
Fig. 1. Induction of VT by electrophysiologic study (EPS) during amiodarone therapy (top panel). Holter monitor performed 1 year later on continued amiodarone therapy shows episodes of slow spontaneously terminating VT (see text).
Table
II. Prospective
indicate
detection
of recurrent
VT by each
technique. complex ventricular ectopic activity. The doses employed and the serum amiodarone levels obtained on chronic therapy in these patients have been in the therapeutic range. In examining the data of Nademanee et al., we have noted that patients No. 2, 5, and 7 did not meet their criteria of 95”U suppression. While we, too, have been impressed by amiodarone’s efficacy in suppressing ventricular ectopic activity as compared to other agents, the degree of success reported herein! is not what we have routinely seen in our experience. Table I summarizes our experience with induction of sustained ventricular tachycardia during chronic electrophysiologic studies. These studies were performed a mean of 32 days after initiation of amiodarone therapy. Amiodarone was administered in a multiple dose schedule in these patients. As can be noted, 7 of 16 patients who had inducible sustained ventricular tachycardia during control electrophysiologic studies were reinducible during the chronic study. However, in a follow-up ranging from 70 to 457 days, four of the seven patients with inducible sustained ventricular tachycardia have had recurrences. In all instances these patients were not hemodynamically compromised during the recurrence, with the arrhythmia being significantly slowed. Fig. 1 illustrates induction of ventricular tachycardia in such a patient during chronic electrophysiologic studies. The ventricular tachycardia is slow and spontaneously terminating. This patient had
almost comp1et.e abolition of ventricular ectopic activity, but Holter monitor performed 1 year later shows episodes of slow spontaneously terminating ventricular tachycardia. in our studies, continuous 24-hour ambulatory monitoring was performed from the initiation of amiodarone therapy until chronic electrophysiologic studies. Serial monitoring was performed at Z&month intervals subsequently. We believe that this intensive monitoring protocol has resulted in the detection of minimally symptomatic and infrequent ventricular tachycardia in our patients. However, we have observed acceleration of this ventricular tachycardia during exercise in the same patient. In cornpar.. ing programmed electrical stimulation performed after 1 month of amiodarone therapy to Holter monit.oring and exercise testing at the same intervals, it is apparent that programmed electrical stimulation is more sensitive and moderately specific (Table 11). Authors reporting on amiodarone have emphasized the discordance between programmed electrical stimulation studies and subsequent clinical results. We consider the limitations of subsequent clinical detection of minimally symptomatic arrhythmias to be an important variable. In reviewing similar data from other studies,
we noted
~4 much
higher
incidence
of recurrent
symptom
atic ventricular tnchycardia in patients who remained inducible on amiodarone therapy.‘,” We think t.hat the difference in arrhythmia recurrence in patients who remain noninducible during chronic electrophysiologic studies as compared to those who do remain inducible may be significant. The limited follow. up and the small number of patients In all our studies preclude a conclusive statement in this regard. We support (;raboys editorial plea for “numerators in search of denominators” an applied t.o programmed eleckrical stimulation studies.” 111 t;jct. studies on :he clinical sensitivity and specificity of programmed electrical stimulation protocols are sorely needed. We ha\fe recently reported that stimulation techniques influence bot,h the cycle length and the morphology of the induced arrhythmia. This is particularly true when complex and aggressive stimulatiun techniques are applied.‘” While the earlier studies utilized comparatively simpler techniques of single and double extrastirnulr and rapid pacing, the specificity of those studies appears 1~ he higher than present techniques that 11se multiple extrastimuli and high-rate ventricular pacing. These induced arrhythmias in the clinical electrophysiology laboratory are frequently hrmodynamically and electrically more unstable than the patient.‘> spontaneous arrhythmia, exposing the patient to a greater need for pharmacologic or electrical termination of the arrhythmia. Wr believe that the question of the sensitivity and specificity of programmed electrical stimulation techniques is important enough to warrant a multicenter cooperative approach for examination of this problem. .Snnjeev Saksena, M.D Stephen 7’. Rothbart. M.1). Gail Cappeilo. R.N. ( ‘urdiac Electrophysiology
Volume
105
Number
1
REFERENCES 1. Nademanee K, Hendrickson J, Kannan R, Singh BN: Antiarrhythmic efficacy and electrophysiologic actions of amiodarone in patients with life-threatening ventricular arrhythof spontaneously-occurring mias: Potent suppression tachyarrhythmias versus inconstant abolition of induced ventricular tachycardia. AM HEART J 103:950, 1982. 2. Saksena S, Rothbart ST, Kaufmann WE, Rathyen W: Chronic electrophysiologic, systemic and pharmacologic effects of amiodarone in recurrent ventricular tachycardia. Am J Cardiol 49:1044, 1982. 3. Saksena S, Rothbart S, Kaufmann WE: Amiodarone in ventricular tachycardia. N Engl J Med 26:1587, 1981. 4. Follansbee WP, Michelson EL, Morganroth J: Nonsustained ventricular tachycardia in ambulatory patients: Characteristics and association with sudden cardiac death. Ann Intern Med 92:741, 1980. 5. Gloor HO, Urthaler F, James TN: The immediate electrophysiologic effects of amiodarone on the canine sinus node and AV junctional region. Am J Cardiol 49:981, 1982. 6. Akhtar M. Shenasa M. Denker S. Gilbert C: Electronhvsiologic effect of amiodarone on His Purkinje conductibn*and refractoriness in man. Clin Res 30:167A, 1982. EN, Jackman WM, Naccarelli GW, 7. Heger JJ, Prystowsky 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 305:539, 1981. 8. Morady F, Scheinman M, Hess D: Amiodarone in the management of patients with malignant ventricular arrhythmias. Circulation 64:IV-36, 1981. 9. Graboys TB: The stampede to stimulation-numerators and denominators revisited relative to electrophysiologic study of ventricular arrhythmias. AM HEART J 103:1089, 1982. 10. Saksena S: Limitations of current techniques for induction of ventricular tachycardia. Clin Res 29:659A, 1981.
REPLY To the Editor: We appreciate the opportunity to respond to Dr. Saksena and his colleagues about their comments on our data on amiodarone in the treatment of life-threatening ventricular tachyarrhythmias, recently published in the JOURNAL.’ The authors raise numerous issues based on their essentially unpublished data from a relatively small number of patients, apparently studied without a stringent protocol and, as the authors themselves indicate, followed for a limited duration of time. Their main contention appears to be that electrophysiologic testing is a more sensitive and reliable technique than serial Holter monitoring in gauging the long-term efficacy of amiodarone; this is an issue that is of crucial therapeutic importance. Unfortunately, the data on which the authors base what are clearly tentative conclusions are very limited and fragmentary. For example, as is evident in their Table I, 24.hour Holter monitoring was carried out (to serve as a control recording) in none of their patients before the initiation of amiodarone therapy. Thus a change effected by the drug intervention short-term or long-term cannot be judged meaningfully. Furthermore, Dr. Saksena and associates emphasize the limitations of the clinical detection of minimally symptomatic arrhythmias as a variable that might explain the observed discrepancy between their data and ours. They attempted to overcome this difficulty (as we did also) by intensive regular Holter monitoring during chronic therapy. However, they do not indicate whether they adjusted amiodarone dosage upwards in those patients in whom they found recurrences of symptomatic or nonsymptomatic ventricular tachyarrhythmias. Failure to do this may possibly
Letters
to the Editor
167
lead one to unjustifiably conclude lack of effectiveness on a given dosage regimen of amiodarone. Adjustment of dosage during chronic therapy is necessitated by the variable nature of the pharmacokinetic properties in different patients.* Dr. Saksena and his colleagues state that “The doses employed and the serum amiodarone levels obtained on chronic therapy in these patients have been in the therapeutic range.” However, they do not indicate what constituted their “therapeutic range” of serum amiodarone concentrations, nor do they suggest how the range of concentrations deemed “therapeutic” was established: Was it the range that was effective in preventing inducible ventricular tachycardia (VT), or that which suppressed symptomatic VT, or was it the one that produced premature ventricular contraction (PVC) suppression of a defined degree? We believe that at present the clinical utility of serum amiodarone level measurements is far from being established. For this reason, adequate which is a function of dose as well as “amiodaronization,” duration of therapy, must be judged on an individual basis since the elimination half-life of the drug is exceedingly variable, perhaps between 15 and 65 days.’ Satisfactory dosage regimes may, however, be developed on the basis of indirect parameter? relative to the attainment of predetermined goals of therapy and the development of side effects. Our experience with this approach now extends to over 250 cases of cardiac arrhythmias resistant to conventional antiarrhythmic agents. Recently we have analyzed our data from our first 96 patients with life-threatening ventricular arrhythmias given amiodarone and followed for a mean period of 15 months (range 6 to 40). In 72 patients, 24-hour Holter recordings have been done before as well as serially during chronic therapy; in 43 such patients, arrhythmia induction by programmed electrical stimulation (PES) was undertaken before as well as after adequate “amiodaronization.” The details are being presented elsewhere,’ but in essence the data extend and confirm those that we’,” and others6 have reported in smaller series of patients. It is clear that when amiodarone is used as a single agent in an appropriate dosage regimen, it predictably eliminates the recurrences of symptomatic and nonsymptomatic VT (previously resistant to conventional therapy) in 80r, to 90”; of patients with life-threatening ventricular arrhythmias; such an effect in our experience is accompanied by P 9O’c suppression of total PVCs on Holter recordings. On the other hand, in up to 50°C of such patients (compared to 7 of 16 patients in Dr. Saksena’s series), VT (sustained as well as unsustained) is inducible by PES. As has been noted by others also,’ we have not !seen significant differences between the clinical course of patients in whom tachycardia was inducible on amiodarone and in whom it was not. As indicated by Dr. Saksena, it is conceivable that minor differences (which will require extremely large numbers of patients to demonstrate) between the subsets of patients in whom inducible VT is sustained and in those in whom it is unsustained on amiodarone may be found. However, such differences, if they exist in the case of amiodarone, are unlikely to be of more than theoretical interest as the drug is clinically effective in the largest numbers of patients to whom it is given. As Dr. Saksena and his associates also confirm, even in patients with inducible sustained VT recurrences of spontaneous VT were not associated with hemodynamic compromise, the arrhythmias being slower and :,elf-terminating. In our experience, the arrhythmia may respond to a slightly higher dose or duration of therapy and is rarely associated with fatality. We are, however, intrigued by Dr. Saksena et al’s observation that in all seven of their patients who had inducible VT, the arrhythmia was sustained. Also surprising is their comment that unlike our findings, they discovered “considerably wider spectrum of effects” induced by amiodarone with respect to electro-