Interactions between drugs and devices: Experimental and clinical studies

Interactions Experimental

between drugs and devices: and clinical studies

It is important to understand the potential interactions between the implantable cardiovetter defibrillator (ICD) and antiarrhythmic therapy in patients who receive pharmacologic therapy as an adjunct to ICD therapy. In our cohort of 101 patients, antiarrhythmic agents were prescribed in 67% of the patients during long-term therapy for the following reasons: to suppress ventricular tachycardia/ventricular fibrillation episodes (SO%), to lower the rate of ventricular tachycardia (19%), to prevent supraventricular tachyarrhythmia (21%), and for other reasons (10%). The potential influence of antiarrhythmic drugs on the defibrillation threshold (DFT) is the most important issue. In animal studies lidocaine increased the DFT in a dose-dependent manner. Quinidine, procainamide, propafenone, and flecainide did not affect the DFT or, in some cases, led to a small increase. Sotalol even decreased the energy requirements for internal defibrillation. In a prospective investigation we were able to document a significant increase of DFT (from 14.1 + 3.0 to 20.9 + 5.4 J, p < 0.001) by the use of amiodarone (400 mglday), whereas this effect was not found in patients who received mexiletine (720 mglday). In conclusion, the DFT or the safety margin for defibrillation should be known before antiarrhythmic agents are administered to patients with an ICD. In case of a small safety margin, the DFT should be reassessed after antiarrhythmic drug therapy is begun. (AM HEART J 1994;127:978-84.)

Matthias

Manz, MD, Werner Jung, MD, and Berndt

The implantable cardioverter defibrillator (ICD) has proved to be a safe and effective alternative to antiarrhythmic drug treatment in patients with lifethreatening tachyarrhythmias.‘-4 Ideally the ICD eliminates the need for antiarrhythmic drug therapy after device implantation. However, a large number of patients are treated with concomitant antiarrhythmic agents. There are several indications for antiarrhythmic drug treatment (see Table I). Antiarrhythmic agents are supposed to decrease the frequency of spontaneous tachycardia episodes and slow the rate of ventricular tachycardia (VT) to avoid syncope before restoration of sinus rhythm. They also prevent patients from experiencing discomfort that results from numerous ICD discharges. In addition, antiarrhythmic drugs may allow successful antitachycardia pacing with newer devices. Furthermore, patients with nonsustained VT may be protected from unnecessary device discharges and early battery depletion. Spontaneous or shock-induced supraventricu-

From the Department of Cardiology, University of Bonn Reprint requests: Matthias Manz, MD, Department of Cardiology, sity of Bonn, Sigmund-Freud-Str. 25. 53105 Bonn, Germany. Copyright ‘I 1994 by Mosby-Year Book, Inc. 0002-8703/94/$3.00

978

+ 0

4/o/53013

Univer-

Liideritz,

MD Bonn, Germany

Table I. Indications and interactions of antiarrhythmic treatment as an adjunct to ICD therapy Indications the incidence of ventricular tachyarrhythmias Avoidance of patients discomfort Avoidance of early battery depletion Avoidance of inappropriate discharges in case of nonsustained VT To lower the rate of VT Avoidance of syncope before conversion of SR To reduce

Making the VT accessible for antitachycardia pacing To influence the pathomechanism of the ventricular arrhythmia such as @-blocker therapy in long QT syndrome or catecholamine-sensitive arrhythmias To suppress supraventricular arrhythmias or to lower the ventricular response during SVT Possible adverse interactions To increase the energy requirements for defibrillation To interfere with the pacing function To impair the detection of ventricular tachyarrhythmias

lar tachyarrhythmias, such as atria1 fibrillation with high-rate ventricular response, may also require drugs to prevent arrhythmias from causing inappro-

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Number of patients [n] 30

1

2520-

151050-mI

1 15%

2% 1

IA

IB

IC

1

III III SOT AMIO Antiarrhythmic agents II

IV

lll+lB

Fig. 1. Concomitant

antiarrhythmic therapy during follow-up in a group of 101 patients. Percentages of antiarrhythmic agents prescribed to patients with an ICD for suppression of ventricular tachyarrhythmias are shown. AMIO, Amiodarone; SOT, sotalol.

priate activation of the ICD system. Because a large cohort of patients receive pharmacologic therapy as an adjunct to use of an ICD, it is important to understand the potential interactions of the ICD and antiarrhythmic therapy (Table 1). Among the potential interactions, the most important concern is the effect of antiarrhythmic therapy on defibrillation threshold (DFT). ANTIARRHYTHMIC TO ICD

THERAPY

AS AN ADJUNCT

Antiarrhythmic agents for the abovementioned indications are prescribed in up to 70% of patients during long-term follow-up. In the series of Echt et al.,l concomitant antiarrhythmic drug therapy was used in 48 of 72 patients (67 % ). The major indications were frequent sustained or nonsustained VT in 22 of 48 patients and recurrent supraventricular tachyarrhythmias in 18 of 48 patients. In a cohort of 270 patients, Winkle et a1.2 used concomitant drug therapy in 69% of the patients to suppress nonsustained or sustained ventricular tachyarrhythmias that might cause frequent device discharges. In addition, atrioventricular node blocking drugs were prescribed for 55 % of the patients. In

another series of 94 patients described by Kelly et a1.,3 antiarrhythmic drugs were needed to control frequent episodes of sustained or nonsustained VT in 49% of the patients. Twenty-six percent of the patients required P-adrenergic blocker therapy for control of maximum sinus heart rate or atria1 fibrillation. In patients with newer ICD devices, class I and class III antiarrhythmic drugs were administered in 38% of the patients, and P-adrenergic blocking and calcium channel blocking agents were administered in 46% of the patients.5 We analyzed concomitant antiarrhythmic therapy during long-term follow-up in a cohort of 101 patients. The protocol was approved by the local Ethics Committee and informed consent was obtained from all patients. Antiarrhythmic agents were prescribed in 67 % of the patients; most received sotalol (Fig. 1). The antiarrhythmic agents were administered to suppress VT or ventricular fibrillation (VF) episodes in 50% of the patients, to lower the rate of VT in 19 % of the patients, and to prevent supraventricular tachyarrhythmias in 21% of the patients (Fig. 2). Although it is common clinical practice to prescribe antiarrhythmic drug therapy to control the

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Not-arrhythmia-related eduction of VTNF-episodes

Reduction of VT-cycle-length

Prevention of supraventricular tachycardias Fig. 2. Different indications for the institution of ant&rhythmic drug therapy during long-term ICD treatment in a cohort of 101patients. Antiarrhythmic drugs were given to control supraventricular tachyarrhythmias in 19 % of the patients, suppress frequent episodes of VT/VF in 50% of the patients, and lower the rate of VT in 21% of the patients.

occurrence of ventricular tachyarrhythmias, it remains unclear whether this practice actually reduces the incidence of ICD shocks. In a cohort of 74 patients with ICD implantation after a single episode of VT/ VF,6 the incidence of ICD discharges was evaluated according to the presence (33 patients) or absence of concomitant antiarrhythmic drug treatment. During a mean follow-up period of 14 months, 46% of the patients treated with antiarrhythmic agents and 44% of patients who did not receive ant&rhythmic agents experienced at least one ICD shock. The amount of time before the first appropriate shock and the frequency of ICD shocks were similar in the two groups. Thus in this study antiarrhythmic agents did not appear to reduce the probability of ICD discharge@; however, antiarrhythmic therapy was not assigned on a random basis. Among other reasons, antiarrhythmic agents were prescribed to suppress VT/VF episodes. Thus the lack of differences between the groups does not exclude an antiarrhythmic effect. In a similar way, the effects of long-term amiodarone therapy on ICD shocks were evaluated in 53 patients during a mean follow-up period of 17.8 months.7 A total of 179 appropriate shocks were registered in 32 % of the patients who took amiodarone, and 126 appropriate shocks were delivered in 29 % of the patients who did not take amiodarone. Thus in these studies a significant number of pa-

tients who received long-term antiarrhythmic therapy continued to experience ventricular tachyarrhythmias and required repeated shocks from the device. The interpretation of the quoted studies is limited by the nonrandomized design of the investigations and by the lack of ICD documentation of arrhythmias. Therefore prospective randomized trials with ICDs equipped with Holter functions are necessary before the benefits of antiarrhythmic agents in suppressing the incidence of VTIVF episodes during long-term ICD therapy can be defined. Antiarrhythmic drug and pacing termination of VT. In the newer ICD devices several arrhythmia zones can be defined and several different therapies, including antitachycardia pacing, can be programmed. According to clinical results a comparably high efficacy rate of antitachycardia pacing in the range of 82 % to 95 % of the VT episodes was observed. Because the efficacy of programmed electrical stimulation is related to the VT cycle length, antiarrhythmic agents can be used to lower ventricular rate. Therefore antiarrhythmic drugs can improve the chances that pacing will terminate ventricular tachycardia by slowing the rate. Since less aggressive stimulation protocols are required in patients with lower VT rates, VT acceleration may occur less frequently.’ In a study of 102 patients who had ICD devices with two-zone tachycardia detection algorithm and both overdrive pacing and low-energy cardioversion

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assigned to the lower tachycardia rates,g 58% received concomitant antiarrhythmic agents. Because the pharmacologic therapy was not described according to a prospective protocol, the contribution of the antiarrhythmic therapy to restoring sinus rhythm through antitachycardia pacing in 79% of the episodes is not yet known. Effects of antiarrhythmic drugs on DFT. Because the energy supply for automatic defibrillation and thus the safety margin of the implanted systems are limited, the influence of antiarrhythmic agents on the energy requirement for defibrillation becomes a crucial issue. Echt et al.1° hypothesized that alterations of DFT by antiarrhythmic agents may result from actions of these drugs on transmembrane sodium and potassium currents. Drugs that alter sodium or potassium conductance might widen the zone between resting membrane and threshold potentials, thus increasing the stimulus strength required to achieve the threshold and initiate an action potential.‘O The influence of individual antiarrhythmic agents on DFT must be known when pharmacologic therapy is begun, especially in caseswith borderline DFT. Because the evaluation of the defibrillation requirements is rather difficult, most of our knowledge of the effects of antiarrhythmic agents on DFT is based on animal data. Lidocaine and lidocaine analogs. The energy requirements for defibrillation of VF were evaluated with use of an internal spring and an epicardial patch electrode in an anesthetized dog model.il Lidocaine doubled the defibrillation energy requirement at a mean plasma concentration of 8.2 pug/ml (p < 0.001). This effect of lidocaine on DFT was reversible and linearly related to the plasma concentration of the substance (p < 0.002). Similar to these findings in normal dog hearts, lidocaine influenced the DFT in the setting of chronic canine infarction: the 50% effective defibrillation (E& voltage increased with lidocaine by 40% (384 -t 99 to 524 t- 108 V, p < 0.001). l2 It could be shown, however, that some of the effects of lidocaine on DFT resulted from interactions between the drug and the anesthesia used.13During implants in humans, lidocaine administered intravenously in a dose of 150 mg did not alter the minimum energy required for defibrillation despite plasma levels of lidocaine that averaged 13.2 f 1.9 pmol/L.14 The effect of mexiletine on DFT has not been evaluated systematically in animals. In a case report study15 the oral treatment with mexiletine was associated with a clinically significant increase of DFT. No controlled animal studies are available to support this observation. In our prospective comparison of

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long-term mexiletine therapy on DFT in menI we did not find a significant effect of the substance on the defibrillation requirement during long-term ICD therapy. Quinidine and procainamide. In dogs anesthetized with pentobarbital, quinidine had no significant effect on energy requirements: mean E50 before and after treatment was 6.3 -+ 3.3 J and 6.2 + 2.9 J, respectively.17 In normal dog hearts, no change of DFT through use of intravenous procainamide was observed.ls In the setting of chronic canine infarction, Es0increased slightly from 383 f 73 to 429 -+ 71 V (p < 0.05). Compared with lidocaine, the effects were far less pronounced in the same model.ll) l2 Propafenone. Conflicting results with respect to the influence of propafenone on DFT were obtained. In a dog studylg intravenous propafenone increased the Es0 and Es0 by a mean of 75 % and 59%) respectively. When the effects of short-term and prolonged administration of propafenone on DFT were determined in pigs,2oDFTs were lower either after shortterm infusion (26 f 6.2 J at baseline and 15.6 * 5 J at 40 minutes [p < 0.051) or long-term administration (17.8 ? 2.6 J vs 12 f 3.2 J on propafenone [p < 0.0021). When the results of the two animal models used to evaluate the effect of propafenone on DFT are compared, the dog model probably bears a higher correlation with findings in humans. Flecainide. The evaluation of different doses of flecainide did not influence the DFT in the pig mode1.21Encainide and its metabolites increased Es0 by 129% + 43% in dogs anesthetized with pentobarbita1.22 Sotalol. DL-sotalol and D-SOtdO decrease the energy requirements for internal defibrillation by approximately 20 % in dogs irrespective of the anesthesia used.23The decrease in DFT and the concomitant prolongation of ventricular effective refractory period with DL-sotalol and D-SOtdO suggest that the type III antiarrhythmic property of sotalol is responsible for the change in energy requirements for defibrillation. Preliminary results in menz4 could demonstrate that energy requirements for defibrillation do not increase during long-term oral therapy with the classIII agent sotalol (control group, 18 ? 3; drug group, 18 * 3). Dorian and Newman25 found a comparable low DFT of 5.9 +- 3.4 J in 25 patients who received sotalol, 171 f 58 mg/day, at the time of ICD implantation. Under sotalol the induction of VF appeared to be more difficult, induced VF had a tendency to terminate spontaneously, and the cycle lengths of VF were significantly greater than in patients who were not given drug therapy. The beneficial effect of class III agents on DFT is supported by

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Energy [Jl

Mexile tine H

Implant

Amiodarone

q

Replacement

Fig. 3. Comparison of the DFT at the time of implantation and at the time of generator replacement. There was no difference in the DFT of patients undergoing long-term mexiletine therapy, whereas the DFT in patients undergoing long-term amiodarone therapy increased significantly.

the findings with clofilium, a drug with relatively pure class III properties.26 Amiodarone. Whereas intravenous application of amiodarone did not change the DFT in an anesthetized dog model, the long-term oral administration of 200 mg/day and 400 mg/day increased the DFT from 7.5 + 0.3 J to 15.4 _+ 0.6 J and 17.9 * 0.8 J, respectively.27 In 11 patients who underwent long-term amiodarone therapy,28 a significant increase of the DFT from 10.9 f 4.3 J at implantation to 20.0 f 4.7 J at replacement (p < 0.05) was found. Comparison of the DFT in patients who took amiodarone at the time of implantation with the DFT in patients who did not take amiodarone7 did not reveal any significant difference. In a prospective, randomized study, the long-term stability of the epicardial DFT was evaluated in 22 patients by Jung et al. l6 The concomitant antiarrhythmic drug treatment consisted of either mexiletine (720 mg/day) or amiodarone (400 mg/day) and was administered to patients in a randomized and parallel manner. During a mean follow-up period of 24 f 6 months, the defibrillation increased significantly from 14.3 + 2.8 to 17.9 F 5.3 J (p < 0.05) for the entire patient group. The increase in the longterm DFT was caused by a marked increase in defibrillation energy needs in the subgroup of pa-

tients who received amiodarone. Whereas no significant change in the DFT was documented in the group of patients who received mexiletine, the mean DFT increased from 14.1 k 3.0 to 20.9 ? 5.4 J (p < 0.001) in patients who received amiodarone (Fig. 3). In all patients with an increased DFT reevaluation showed a reduction in the DFT after discontinuation of antiarrhythmic drug therapy. The only variable associated with an increase in long-term DFT was amiodarone treatment. It appears that amiodarone causes a short-term reduction in the DFT but may cause a long-term DFT increase. The specific pharmacokinetics of amiodarone and its metabolites provide an explanation for the delayed onset of its antiarrhythmic action and may explain the increase in DFTs in patients who receive long-term amiodarone therapy.16 Verapamil. Because the ICD cannot discriminate between rapid ventricular and supraventricular rhythms, verapamil is often prescribed for patients with these symptoms to avoid device discharge for supraventricular tachyarrhythmias, which occur commonly. The influence of verapamil on defibrillation energy requirements is therefore of importance. In an experimental model with anesthetized dogs who had functionally normal hearts, the DFT was evaluated under the influence of intravenous verap-

Volume 127, Number 4, Part 2 American Heart Journal

amil.2g Verapamil administration infused to a mean plasma concentration of 69 rig/ml increased the 50 % and 90 % effective defibrillation energies by 41% and 43 y0 (p < 0.05), and verapamil infused to a mean plasma concentration of 170 rig/ml increased these energies by 95 % and 75 % (p < O.Ol), respectively. A similar effect was documented in humans: verapamil increased the minimum energy necessary for defibrillat,ion from 3.9 -+ 2.2 J to 6.5 +- 2.9 J; the difference in defibrillation energy was correlated to the fall in systolic blood pressure.i” The mechanism by which verapamil exerted this effect remains unclear. Data on long-term verapamil treatment are still lacking.

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of the electrical device must be ruled out before antiarrhythmic treatment is started. The influence of antiarrhythmic agents on the energy requirement for defibrillation is the most important concern. Thus the DFT or the safety margins for defibrillation in the individual patient should be known before antiarrhythmic treatment is prescribed. In case of a high DFT, the influence of antiarrhythmic therapy on the defibrillation energy requirement should be reassessed after antiarrhythmic treatment is begun. Because of the delayed onset of action of amiodarone, threshold evaluation should be performed 3 to 4 weeks after treatment is begun. REFERENCES

ANTIARRHYTHMIC FUNCTION

DRUGS AND PACEMAKER

It is well known that antiarrhythmic agents can alter the intracardiac signals and the pacing threshold, thereby impairing arrhythmia detection and pacing function.“O In therapeutic levels, class IA and IB agents do not cause a clinically significant effect on ventricular pacing thresholds, whereas class IC agents show a pronounced increase of the pacing threshold under short-term and long-term therapy.31 Oral amiodarone therapy does not alter pacing threshold and time to ventricular capture after shock delivery in patients.32 In case of shock delivery through an ICD, the intracardiac signals can be reduced in amplitude and the after shock threshold for stimulation increases, possibly resulting in temporary loss of ventricular capture. These problems can be anticipated with newer devices that automatically increase the stimulus strength after the shock. In case of borderline threshold, however, the influence of antiarrhythmic drugs must be considered and assessment of detection and stimulation thresholds is mandatory if the antiarrhythmic agents are begun.33, 34 CLINICAL

1

2

3

4.

5.

6.

7.

720-l. 8. Naccarelli

IMPLICATIONS

Clinicians must be aware of the possible benefits and detrimental consequences of the interactions between antiarrhythmic agents and implantable defibrillators. In case of recurrent episodes of ventricular arrhythmias, antiarrhythmic agents are indicated. It should be kept in mind, however, that suppression of VT/VF episodes cannot be expected in every patient. The unpredictability of VT/VF recurrences in conjunction with a clustering of episodes (“storming”) makes it more difficult to assess the contribution of antiarrhythmic therapy. In any case other initiating events such as electrolyte disturbances, ischemia, and, last but not least, malfunction

Echt DS, Armstrong K, Schmidt P, Oyer PE, Stinson EB, Winkle RA. Clinical experience, complications, and survival in 70 patients with the automatic implantable cardioverter/ defibrillator. Circulation 1985;71:289-96. Winkle RA, Mead RH, Ruder MA, Gaudiani VA, Smith NA, Buch WS, Schmidt P, Shipman T. Long-term outcome with the automatic implantable cardioverter-defibrillator. J Am Co11 Cardiol 1989;13:1353-61. Kelly PA, Cannom DS, Garan H, Finkelstein D, McComb JM, Mirabal GS, Ilvento JP, Ruskin JN. Predictors of automatic implantable cardioverter defibrillator discharge for life-threatening ventricular arrhythmias. Am J Cardiol 1988;62:83-7. Gabry MD, Brodman R, Johnston D, Frame R, Kim SG, Waspe LE, Fisher JD, Furman S. Automatic implantable cardioverter-defibrillator: patient survival, battery longevity and shock delivery analysis. J Am Co11 Cardiol 1987;9:1349-56. Wietholt D, Block M, Isbruch F, Backer D, Hammel D, Borggrefe M, Scheld HH, Breithardt G. Therapie ventrikularer Tachyarrhythmien mit implantierbaren Kardioverter/Defibrillatoren-Sterblichkeit und Komplikationen bei der Verwendung epikardialer Elektroden. Z Kardiol 1993;82:150-61. Kou WH, Kirsh MM, Bolling SF, Stirling M, Kadish AH, De Buitleir M, Calkins H, Lewis RR, Morady F. Effect of antiarrhythmic drug therapy on the incidence of shocks in patients who receive an implantable cardioverter defibrillator after a single episode of sustained ventricular tachycardia/fibrillation. PACE 1991;14:1586-92. Huang SK, Tan de Guzman WL, Chenarides JG, Okike NO, Vander Salm TJ. Effects of long-term amiodarone therapy on the defibrillation threshold and the rate of shocks of the implantable cardioverter-defibrillator. AM HEART J 1991;122:

9.

GV, Zipes DP, Rahilly GT, Heger JJ, Prystowsky EN. Influence of tachycardia cycle length and antiarrhythmic drugs on pacing termination and acceleration of ventricular tachycardia. AM HEART J 1983;105:1-5. Fromer M, Brachmann J, Block M, Siebels J, Hoffmann E, Almendral J, Ohm O-J, den Dulk K, Coumel P, Camm AC, Touboul P. Efficacy of automatic multimodal device theranv for ventricular tachyarrhytbmias as delivered by a new implantable pacing cardioverter-defibrillator. Circulation 1992;

86:363-74. 10. Babbs CF. Alteration

of defibrillation threshold by antiarrhythmic drugs: a theoretical frame work. Crit Care Med 1985;9:362-3. 11. Echt DS, Black JN, Barbey JT, Coxe DR, Cato E. Evaluation ^ . . or antiarrhythmic drugs on defibrillation energy requirements in dogs: sodium channel block and action potential prolongation. Circulation 1989;79:1106-17. 12. Ware DL, Atkinson JB, Brooks MJ, Echt DS. Ventricular defibrillation in canines with chronic infarction, and effects of lidocaine and procainamide. PACE 1993;16:337-46.

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13. Natale A, Jones DL, Kim YH, Klein GJ. Effects of lidocaine on defibrillation threshold in the pig: evidence of anesthesia related increase. PACE 1991;14:1239-44. 14. Jones DL, Klein GJ, Guiraudon GM, Yee R, Brown JE, Sharma AD. Effects of lidocaine and verapamil on defibrillation in humans. J Electrocardiol 1991;24:299-305. 15. Marinchak RA, Friehling TD, Kline RA, Stohler J, Kowey PR. Effect of antiarrhythmic drugs on defibrillation threshold: case report of an adverse effect of mexiletine and review of the literature. PACE 1988;11:7-12. 16. Jung W, Manz M, Pizzulli L, Pfeiffer D, Ltideritz B. Effects of chronic amiodarone therapy on defibrillation threshold. Am J Cardiol 1992;70:1023-7. 17. Dorian P, Fain ES, Davy JM, Winkle RA. Effect of quinidine and bretylium on defibrillation energy requirements. AM HEART J 1986;112:19-25. 18. Deeb MC, Hardesty RL, Griffith BP, Thompson ME, Heilman MS, Myerowitz RL. The effects of cardiovascular drugs on the defibrillation threshold and the pathological effects on the heart using an automatic implantable defibrillator. Ann Thorat Surg 1983;35:361-6. 19. Peters W. Gans ES. Okazaki H. Solineen S. Kobavashi Y. Karagueuzian I%, Mandel WJ. Acute effects’of intravenous propafenone on the internal ventricular defibrillation threshold in the anesthetized dog. AM HEART J 1991;122:1355-60. AS, Bombardieri G, Barilaro C, Kim YH, 20. Natale A, Montenero Klein GJ, Jones DL. Effects of acute and prolonged administration of propafenone on internal defibrillation in the pig. AM HEART J 1992;124:104-9. 21. Szabo TS, Jones DL, McQuinn RL, Klein GJ. Flecainide acetate does not alter the energy requirements for direct ventricular defibrillation using sequential pulse defibrillation in pigs. J Cardiovasc Pharmacol 1988;12:377-83. 22. Fain ES, Dorian P, Davy JM, Kates RE, Winkle RA. Effects of encainide and its metabolites on energy requirements for defibrillation. Circulation 1986;73:1334-41. 23. Wane M. Dorian P. DL and D sotalol decrease defibrillation energy requirements. PACE 1989;12:1522-9. 24. Kiihlkamp V, Mermi J, Mewis C, Braun U, Seipel L. Long-

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term efficacy of D/L sotalol in patients with drug refractory ventricular tachyarrhythmias and an implantablecardioverter-defibrillator lAbstract1. Eur Heart J 1993:14(Sunn11:410. Dorian P, Newman D. Effect of sotalol on ventri&lar fibrillation and defibrillation in humans. Am J Cardiol 1993;72:72A79A. Dorian I’, Wang M, David I, Feindel C. Oral clofilium produces sustained lowering of defibrillation energy requirements in a canine model. Circulation 1991;83:614-21. Frame LH. The effect of chronic oral and acute intravenous amiodarone administration on ventricular defibrillation threshold using implanted electrodes in dogs. PACE 1989: 12:339-46. Guarnieri T, Levine JH, Veltri EP, Griffith LS, Watkins LJ, Juanteguy J, Mower MM, Mirowski M. Success of chronic defibrillation and the role of antiarrhythmic drugs with the automatic implantable cardioverter/defibrillator. Am J Cardiol 1987;60:1061-4. Schriider R, Brooks M, Echt DS. Effects of verapamil and Bay K 8644 on defibrillation energy requirements in dogs. J Cardiovasc Pharmacol 1992;19:839-50. Singer, Guarnieri T, Kupersmith J. Implanted automatic defibrillators: effects of drugs and pacemakers. PACE 1988; 11:2250-62. Barold SS, McVernes R, Stokes K. Effects of drugs on pacing threshold in man and canines: old and new facts. In: Barold SS, Mugica J, eds. New perspectives in cardiac pacing. Mount Kisco, N.Y.: Futura, 1993:57-83. Khastgir T, Lattuca J, Aarons D, Murphy J, O’Mara V, Juanteguy J, Veltri EP. Ventricular pacing threshold and time to capture postdefibrillation in patients undergoing implantable cardioverter-defibrillator implantation. PACE 1991;14:76872. Reiffel JA, Coromilas J, Zimmermann JM, Spotnitz HM. Drug-device interactions: clinical considerations. PACE 1985; 8:369-73. Tworek DA, Nazari J, Ezri M, Bauman JL. Interference by antiarrhythmic agents with function of electrical cardiac devices. Clin Pharm 1992;11:48-56.