Safety Margins: Lessons from the Low Energy Endotak Trial (LEET)

Safety Margins: Lessonsfrom the Low Energy Endotak Trial (LEET) Jorg Neuzner,

MD

The low Energy EndotakTrial (1.EET) was designedas a prospective,randomized, muhicenterstudy to evaluate the efficacy and safety in nonthoracotamycardioverterdefibrillatar therapy with lower d~brillation energies compared to the conventional programming with devicesset at maximum output. Between December 1993 and January 1996, 172 consecutivepatients, undergoing implantation of a biphasiccardiove~r-d~brillatar with a single endocardial defibrillation lead system, were screenedfar studyenrollmentin 4 Europeanstudy centers. Study inclusioncriteria were defined as documented ventricular fibrillation, polymorphic ventricular tachycardia, or fast, hemadynamically unstableventricular tachycardia, unresponsiveto antitachycardia pocing and an augmented defibrillation threshold (DFT+) s 15 Joules (J). Patients presenting slow, pace-terminable ventricular tachycardias were excluded. Patients were randomized into 2 study arms: (1) test graup potients: the first-shockenergy of ihe implanted devices was programmed at 2 x DH+, the second to fifth shocksat maximum output (34 J); (2) controlgroup potients:all shockswere programmed at 34 J. Ventricular fibrillation (VF) conversion tests (first shock energy DFT+; secondshock2 x DFT+) were performed in test group patients intraopemtively, during predischarge test, and after 12 monthsfallow-up. In the controlgroup patients, the arrhythmia conversion tests were performed with maximum device output (34 J). S~ntcme-

oustachyarrhythmia episodeswere classifiedby stared intracardiac electragram analysis, and conversionrates were compared between the 2 studygroups. CMthe 172 screenedpatients, 162 (94’%.) met the inclusioncriteria and were enrolled in the study. The mean DFT+ was 9.6 ~ 3.2 J in the test group and 10.0 * 3.5 J in the control group. The successrate far the test group for a repeated arrhythmia conversiontestat DFT+ was 84.4Y0 (157 of 186 inducedVF epiiodes); the cumulative successmte far the first and the secondshockswas 99. 5Y0 (185 of 186 inducedepisodes).In the controlgroup, the firs~shockconversionrate at 34 J was 98.8% (158 of 160 induced episodes). During a mean fallow-up of 10 t 7 months, the first-shackconversionrate for spontaneousarrhythmia episodeswas 98.5% (65 of 66 episodes) in the test group patients and 92~0 (69 of 75 episodes)in control group patients (p >0.05). Analyzing the pooled data of spontaneousand induced arrhythmia episodes,there were no differencesregarding the first shockconversionrate between the 2 groups (test group: 98.4%; control group: 96.6%; p >0.05). The overall mortality was 3’%., equai~ distributed in both groups.The preliminary resultsof thisstudysuggestthat over a 1-year period, the “2 x DFT+” safety margin was equally effectiveas the margin provided by a 34-J device far conversion of induced and spontaneous tachyarrhythmia episodes. (Am J Cardiol 1996;78(suppl 5A):26-32)

he implantable cardioverter-defibrillator (ICD) has proven safe and effective in the treatment of T patients with recurrent life threatening ventricular

measured acute defibrillation threshold (DFT). Therefore, the level of methodologic accuracy mandatory in defibrillation testing is not well defined, nor has the level of DFT necessary to ensure chronic device efficacy been established. As a further major factor, the progress in ICD technology may have a significant impact on the extent and method of intraoperative defibrillation testing during implantation of an ICD. In December 1993 a prospective and randomized multicenter study (Low Energy Endotak Trial, or LEET) was started to evaluate a new method of determining adequate energy safety margins with lower defibrillating energies, using today’s lead and implant techniques. This report will review the preliminary results of the LEET study at 2 years. The efficacy of this method to estimate adequate safety margins in defibrillator therapy will be presented. These results may have significant impact on the method and the extent of intraoperative device testing. We will also present a modified protocol of intraoperative defibrillation testing, which provides the evaluation of adequate safety margins for chronic endocardial, biphasic defibrillator therapy using only a few fibrillation/defibrillation attempts.

tachyarrhythmias.1-6The clinical long-term success of the therapy depends mainly on the device’s ability to terminate malignant ventricular tachyarrhythmias over time under changing clinical circumstances. During implantation of an ICD, testing is mandatory to establish adequate detection and termination of ventricular fibrillation (VF). Beyond the evaluation of the acute efficacy, testing procedures are required to ensure reliable defibrillation in the future. There is a significant variability in current clinical fibrillation–defibrillation testing procedures,7 and “to date there has not been a universally accepted ‘gold standard’ for assessing defibrillation efficacy or a ‘safety margin.’ 8 There are no prospective clinical studies that have been able to demonstrate any relationship between patients’ outcome and the intraoperative From theMox Plonck Institutefor Physiological and Clinical Reseorch. Address for reprints: Jorg Neuzner, MD, Dept. of Cardiology, Mox Planck Institute for Physiological and Clinical Reseorch, Kerckhoff
26

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DEFIBRILLATION DOSE-RESPONSE CURVE In cardiac defibrillation it is not possible to define a sharp limit or threshold in terms of voltage, current, or energy below which no successful defibrillation will occur and above which defibrillation consistently results in termination of VF.9-11Despite a given theoretical constancy of all variables, the factor of biovariability is the reason that the relation between defibrillation success and shock strength is best described by a sigmoid-shaped dose–response curve (Figure 1).9’12Shock strengths located on the upper slope of the curve have a higher probability to terminate VF; shock strengths located at the intermediate or lower part on the curve will not achieve conversion of VF all the time. Determination of an actual defibrillation dose-response curve requires >30 fibrillation/defibrillation episodes,9,10,1 s-15and therefore it is not clinically feasible. Determinants of defibrillation dose–response curves have been described in several investigations.g’10’13’16 These results suggest that the full width of the curve can be expressed in a specific range of energies, or as a multiple of the curve’s midpoint energy, i.e., that energy providing 50% defibrillation success. To assure defibrillation efficacy and resulting energy safety margin of an ICD, it is necessary to verify that programmed shock energy is located high enough on the dose-response curve to provide 100Yodefibrillation success. A defibrillation testing protocol for an ICD implantation should provide a maximum of information on the patient’s individual defibrillation dose–response curve to ensure an accurate assesment of defibrillation efficacy and safety margins while reducing the total number of fibrillation/defibrillationattempts for patients’ safety.

100 80

‘P:v+--v”

I

F

Measured

20 ~-

;~

EDcm —; Margin

o 0

5

10

15

20

E (jOUk@ ~ FIGURE 1.Thedefibrillation dose-response CUM showsthe relaof successful ants miaconvertion betweenpercentprobability sionversusdei%riltationenergy. Themeasureddel’”brillation success asa rethreshold(~ indicamsthe lowestcarctioversion sultofa givendefibrillation testingprotocol. Thedifference in cfefrbrilkrtionenergyfrom the paint of defibrillationsuccess bility to a progmmmedone Theevaluation of an $~~ess*is~al~~’’~pmwdiqa acy margin.”l~defibri=efficacymarginde ndsmainfyon b accumcyof M measwe-+adb4dks~m*lMMlMon &w-m~nsa cwrve,An odequ~ s%cocymargin is necessa7 ta provideconsisisntdetlbrilfohn efficacyfar any numberof replimtive fibrilfation/deHxillotion testingepisodesduring deviceimptantotion. Thedifferencefrom the energy level pravidi~ 100% defibrillation successduring im Iantationand k pragmmmed cWce ene~ou~iscalM$eJ/* tiqinYrfie*~m~in shouldassuredevicefficy fbr variousclinicalcircums~nces, which may lead to a shiftin a given patient’sdefibrillationdoseres nsecurve. @doptedwith kind permissionfrom I. Singer anr D. J. 1.cmg.9)

animal studies indicate that the width of the defibrillation dose–response curve can be expressed as a multiple of the defibrillation threshold energy.10’16 An energy efficacy margin that ensures a 100% defibrillation success will require the defibrillating energy to be programmed to 1.7–2.0 times the D~.9’18 Augmented DFT testing protocols will provide DEFIBRILU4TION TESTING PROTOCOLS:ESTIMATIONOF SAFETY higher accuracy in the estimation of safety margins.9’22The successful reconfirmation of .a defibrilMARGINS Numerous methods for clinical defibrillation test- lation attempt at the previously determined DFT, ing have been described in terms of protocols veri- called “DFT+” energy, will define the lowest enfying efficacy, DFT, and the upper limit of vulner- ergy on the defibrillation dose-response curve in the ability.10,11,13,14, ]6-21The discussion of all reported range of 50$%success probability. Therefore the efmethods or protocols for assessment of defibrillation ficacy margin will be consistent with an energy proefficacy is far beyond the scope of this article. Rel- grammed at 1.5 times the augmented defibrillation ative to the LEET study, defibrillation step-down threshold (DFT+). 22 The efficacy and Safety of testing protocols and one type of enhanced or aug- these methods to assess defibrillation safety margins mented step-down testing protocol will be discussed have never been studied under the conditions of a briefly. The step down defibrillation testing protocol controlled randomized clinical study, and particuconsists of a sequence of fibrillation/defibrillation larly not with today’s lead and device technology. trials with a subsequent reduction of the defibrilla~ tion energy after each successful termination of VF. CLINICALDATA ON DEFIBRILLATION The lowest energy providing termination of VF is ENERGYSAFETYMARGINS IN ICD defined as the DFT. The accuracy of this method to THERAPY Uncertainties exist on how to perform accurate determine the location of a tested defibrillation energy on the defibrillation dose–response curve de- and rigorous intra-operative defibrillation testing. pends on the possible extent of the DFT distribution Historically, the defibrillation safety margin for imon the curve. It has been demonstrated that step- plantation of an ICD was based on a “10 Joule (J) down DFT results are located near the level of a 75% rule.” This rule of thumb was reported by Marchlindefibrillation probability, with a maximum range ski et a123in 1988 in patients undergoing implantadown to a 25% defibrillation success.lO’llResults of tion of ICDS with epicardial lead systems, and A SYMPOSIUM:

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showed that failures of ICDS to terminate VF could only be observed in patients with a defibrillation efficacy margin s 10 J. Although these 1O-Jmargins were empirically derived, they have subsequently been shown to be safe and effective, since several studies have shown that sudden cardiac death is a very rare event in ICD patients with nonthoracotomy lead systems adhering to the 1O-Jrule.3’24-2G Significant technological improvements in ICD therapy— such as new, optimized nonthoracotomy lead systems and biphasic waveform—have led to a reduction in overall DFTs compared to the initial results using nonthoracotomy lead systems. Therefore the technical progress in recent years has led to a substantial increase in the energy margin between clinically obtained DFTs and maximum device output. The clinical results in chronic ICD therapy are consistent with the possibility of providing adequate defibrillation energy safety margins with lower programmed shock strength or the use of smaller devices with lower maximum energy outputs. Every investigational center has its own clinical experience regarding the efficacy of lower defibrillationenergies, but there are no controlled clinical data proving the efficacy and safety of lower defibrillation energies compared to conventionally programmed maximum device output. Furthermore, there are uncertainties regarding the temporal stability of DFTs using nonthoracotomy ICD lead systems,zT-sOme necessity of a controlled, randomized study to evaluate major clinical aspects associated with anew method for the determination of adequate ICD defibrillation energy safety margins was the main reason to conduct the LEET study.

LEET:STUDYOBJECTIVES, PATIENTS, AND METHODS The LEET study was designed as a prospective, randomized, multicenter investigation. The purpose of this study was to evaluate effective defibrillation energy safety margins for a single endocardial defibrillation lead system with ICDS providing biphasic wavefoms and constant energy delivery. Despite the fact that retrospective studies have indicated an association between lower defibrillation energy margins and an increased risk for arrhythmia-related death in ICD patients,31’32no data from controlled studies provide evidence for any relationship between the results of intraoperative defibrillation testing and sudden cardiac death rate. The fact that monomorphic ventricular tachycardia, and not VF, is the main arrhythmia precipitating device discharge, 33and that a clinical arrhythmia is not terminated by only a single shock, but sometimes up to 4 consecutive discharges, may serve as an explanation for the loose relationship between intraoperative test results and sudden cardiac death rates in patients with ICDS. On’the other hand, a clear relationship has been demonstrated between first shock failures and higher intraoperative DFTs.34These studies suggest that the first-shock conversion rate, rather than &dden death mortality, may be a more sensitive 28

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measure for evaluating the clinical efficacy of ICD energy margins. Therefore, the LEET study used initial device conversion rates for induced and spontaneous rhythms as primary endpoints. On an intention-to-treat basis, consecutive patients undergoing ICD implantation were enrolled at 4 European study centers (Appendix). Patients presented with drug refractory life-threatening ventricular tachyarrhythmias. Inclusion criteria were defined as ( 1) documented VF, polymorphic ventricular tachycardia, or fast monomorphic ventricular tachycardia, unresponsive to antitachycardia pacing; (2) implantation of a Ventak PRx II or Ventak PRx III pulse generator (CPI, St. Paul, MN, USA); (3) use of a single endocardial defibrillation lead alone (Endotak, CPI); and (4) DFT+ (augmented defibrillation testing protocol) s 15 J. Patients presenting slow, pace-terminable, monomorphic ventricular tachycardia were excluded, as well as patients with elevated DFTs (DFT+ >15 J). Patients undergoing a pulse generator replacement procedure for a previously implanted Ventak/Endotak ICD system were also excluded. Prior to implantation the patients were randomized in 2 different study arms: ( 1) control group: the energy of all defibrillation pulses was set at maximum output (34 J); (2) test group: the first shock energy was set S2 x DFT+, the energy of the second to fifth shock was programmed at maximum output (34 J). A normal step-down defibrillation testing protoco19 was performed, beginning at 15 J with stepwise energy decrement down to 5 J or until the first failure occurred. The DFT was defined as the last tested energy providing successful conversion of VF. To perform an augmented defibrillation testing protocol (DFT+), it was mandatory to reproduce a further successful conversion of VF at the DFT energy. If this additional test failed, and a second test succeded at 1 step higher energy, this higher energy level was considered to be the DFT+. Every patient underwent a predischarge test with a VF conversion test, and an additional test 12 months after implantation. During these VF conversion tests, patients in the test group had the energy of the first shock programmed at DFT+, and of the subsequent (second) shock at 2 X DFT+. In the control group, all VF conversion tests were performed using the maximum device output, 34 J. During the 12-month follow-up period, each spontaneous arrhythmia episode was analyzed, the underlying arrhythmia was classified using stored electrograms from the implanted ICDS, and the sequence and outcome of electrical therapy was documented.

PRELIMINARY RESULTS OF LEET LEET was started in December 1993, enrollment was finished in January 1996, and the study will end January 1997. The mean follow-up to date is 10.2 t 7 months. A total of 172 patients were screened for study enrollment; 162 patients (94%) met the inclusion criteria reauirhuz an intraoperative DFT-t of s15 J on a singl~ End&dc lead. The pa5A)

SEPTEMBER

12,

1996

j TAME I The Low Energy Endo+akTrial[LEET)-PatienlDemographics[n Test Group Parameter

All Patients

(n=

= 162]

Control

Group

(n=

83)

79)

Male

84.3%

79.5%

87.3%

CAD

64%

60.2%

69.6%

Age (yeors]

57.6

~ 12

56.7

+ 12

57.8

t

12

LVEF (%]

36.6

? 14

38.2

f

35.5

t

14

14

Cardiac arrest

62.8%

61 .4%

64.6%

AA drugs

54.7%

50.6%

59.5%

NYHA

Ill

DFT+

(J)

30.2% 10.4

9.6

NS NS NS NS NS NS NS NS

3 1.6%

27.7%

? 4.2

p Value

* 3.2

10.0t

3,5

AA drugs = antiarrhythmic drugs; CAD = coronary artety disease; NYHA = clinical classification according ta the New York Heart Association; DFT+ = defibrillation threshold measured by an augmented defibrillation testing protocol (see text for further explanation); NS = nonsignificant. Numbers are expressed as mean t SD.

tients’ demographics are summarized in Table I and are comparable to previously reported ICD patient groups. As seen from Table I, there were no statistical differences observed between the test and the control group. The distribution of measured intraoperative DFT+ values is shown in Figure 2. The mean DFT+ was 10.4 ~ 4.2 J. In 71?loof all study patients a DFT+ s1O J could be achieved. The results of the induced-an-hythmiaconversion tests in the test group patients during predischarge investigation and during the 12-month follow-up investigation test can be used to evaluate the reproducibility of successful defibrillation attempts at dif~ ferent DI?T+ energy levels (5, 8, 10, and 15 J). In patients with an intraoperative 5-J DF”T+,a successful VF conversion test at a’5-J defibrillation energy was obtained in 26 of 35 induced VF episodes (74%). In patients with an intraoperative 8-J DFT+, successful VF conversion at 8 J was achieved in 43 of 48 induced VF episodes (90%). At the 1O-Jand 15-J DIW+ level, the percentages of successful VF conversions were 7870 (51 of 65 induced VF episodes) and 97Y0(37 of 38 induced VF episodes), respectively. The overall success rate for a repeated VF conversion test at DFT+ energy level was 84.4%

(157/186 induced VF episodes). In the 29 of 186 induced VF episodes the first shock, programmed at DFT+, failed (Figure 3). In 28 of these 29 conversion tests the second shock, programmed at 2 X DFT+, achieved successful termination of VF. Therefore, the cumulative success rate of the first shock programmed at DFT+ and the subsequent, second shock programmed at 2 X DFI’+ was 99.5?Z0 ( 185 of 186 induced VF episodes). In control group patients (VF conversion tests at 34 J), the first 34-J shock achieved conversion in 158 of 160 conversion tests (98. 8Yo)(Figure 3). In the 2 episodes where the first shock failed, the arrhythmia was successfully converted by the second 34-J discharge. The statistical analysis revealed no differences between the conversion rate S2 x DFT+ and at programmed maximum energy of 34 J for the induced episodes (p = 0.44). During a mean follow-up of 10.2 t 7 months, there were a total of 134 treated spontaneous arrhythmia episodes in 34 patients: 17 test group patients experienced 66 arrhythmia episodes, with 26 episodes classified as VF and 42 as fast monomorphic ventricular tachycardia (MVT). In the control group, 75 episodes occurred in 16 patients: 21 ar-

40%

~= 162

n= 10 30%

1

I I

25”h

FIGURE2. Distributionof de6brilkstion thresholds‘(~. Out of 172 patients, 162 (94%) fulfilledthe inclusioncrileria of on ougmeniedW (DFT’+)<15 Josdes(J).Ten tients with DFT+ >15 J were excruded from data analysis.h distribution of DFT+ valuesshowsthat 71% of all ISSsted patientsshoweda DFT+ <10 J.

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1 ,

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55

I

m

<15

<10

mean DFT+10.4* 4.2J

>15 DFT+ [Joules]

I

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1

100,0%,’

FIGURE3. Conversionratesfar inducedpalymwphicventriculartachycardia/veniricsslorfibrillationepisod4s. In test raup patients*e left bar resentst?e conversionmk for

- So,o”.‘“ $ i Q 60,0% ~ 3 z

::~:$=:~~;:::::;~d (DIT+). The secondbar presentsthe cumulativeconversionrate for the firstshack(DFT+)and the second shackprogmmmedat S2 x DH+.

40,0%

!YLOZ!tYie?;;;;t;kO~~ershockand the cumulativeconversion mte for the firstand second34 J are presenkd.

20,070

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TEST GROUP

l,t.,b.-34J

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CONTROL GROUP

FIGURE4. Conversionmtes br spantaneow arrhythmiaepisodes.The documentedconversionmtes far ‘~b?s *orphiC Ventricular tachycomho/ventricukrr fibrillation (PW/VF) and monomorphicventricular tachycardia(MW episodesin the testgmup are iven by ke two left bars. TherightL rs presentsthe conversionmiw for spontaneousPVT/VF and MVT episodesin the control group patients.

PvTivF m TEST GROUP (n=17/S3)

PvTm m CONTROL GROUP (n-lS179)

rhythmia episodes were classified as VF and 54 as M-VT. The results regarding the first-shock conversion rates in both study groups are summarized in Figure 4. The conversion rate for MVT in the test group patients was 95% (40 of 42 spontaneous episodes). The first-shock conversion rate for VF was 96Y0 (25 of 26 episodes). In control group patients the first-shock conversion rate for MVT was 94Y0(51 of 54 episodes ) and for VF was 86Y0 (18 of 21 episodes). Thus, the preliminary results of documented spontaneous episodes in this study indicate no significant differences between the test and control groups (Figure 4), but definitive confirmation will require analysis for the total sample size of the study. Using the pooled data of induced and spontaneous arrhythmia episodes (Figure 5), the first shock conversion rates were not significantly different between test and control group patients (p = 0.15). No perioperative death occurred in either patient group. The overall mortality during the 10-month follow-up was 3Y0.Two cardiac deaths occurred in the test group, including 1 sudden cardiac death. In the control group there were 30

THE AMERICAN JOURNAL OF CARDIOLOGY”

3 deaths, 1 sudden cardiac death, 1 nonsudden cardiac death, and 1 noncardiac death.

LESSONSFROM THE LOW ENERGY ENDOTAKTRIAL There are 4 general areas in which conclusions can be inferred from the results of the LEET study: ( 1) DFT distribution; (2) reproducibility of conversion at the DFT+ energy over time; (3) validation of the 2 x DFT margin; and (4) recommended clinical testing protocols. (1) LEET demonstrates that DFTs s1O J could be achieved in the majority of patients (71%) undergoing implantation of a single Endotak lead system and a biphasic pulse generator with a mean DFT+ of 10.4 t 4 J. This distribution of measured DFT values justifies the clinical use of 15 J defibrillation energy as the starting energy for defibrillation efficacy measurements, instead of 20 J, which was the common procedure in the past. The advantage of this new starting point is fewer fibrillation/defibrillation episodes without any loss in methodologic accuracy.

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FIGURE5. Conversionmtes lb inducedand spontaneouse isodes. Theconversionmtes for arI arrhythl%%%w’%;zr~ the two bars on the sideof the fi ure. The conversionrate for all ep“SC&s, classifiedas orphicventricular iachycardia P~ and ventricularfibrillation (w), is given by the firstbar on the left side.Theconversionrate for all episodes,includingspontaneousmanamorphicventriculartachycardio (MVll episodesis given by the secondbar on the left side. Thecon~rsion mtes for canlral group pct(nm-r+Pvrm)

(PvTNq

Z

xDFT+

TEST GROUP

m-fm

3dJ

(Mvr+rvT/vF)

&!!:?~

;h~=?~e~?..

CONTROL GROUP

(2) The repeated VF conversion test at different times after initial intraoperative determination of DFT demonstrated a high probability of consistently successful termination of VF. These results indicate that the augmented DFT protocol (DIW+ ) is a very robust testing technique in that it consistently identifies the shock strength at the upper part of the defibrillation dose-response curve. Until today, the number of the repeated VF conversion tests is still not sufficient to achieve statistical significance, but there is a trend showing that the conversion success rates at the DFT+ energy,levels remain unchanged during a 12-month period. This could be interpreted as an indicator that no clinically relevant shift in the defibrillation dose–response curves had occurred in this population of patients. (3) The preliminary results of this study indicate that the device conversion efficacy (i.e., the conversion success with the first or second shock from the device) for the test group with defibrillation energies S2 x DFT+ were not significantly different from the control group, whose devices had been set at the maximum output of 34 J. This suggests that over the l-year period of the study, the 2 X DFT+ margin was equally effective as the margin provided by a 34-J device for conversion of induced and spontaneous tachyarrhythmic episodes in this ICD patient population. (4) Using the DFT+ protocol during implant can reduce the number of VF conversion attempts required for implant and possibly reduce the time for the implant procedure. Adequate energy margins for a 29–34 J device could be assessed with 2–3 conversion tests. A typical 2-shock sequence would involve 2 conversion successes at 15 J. If one wanted to better characterize the DFT for the patient, one could test 1 conversion attempt at 15 J and a second at 10 J. If the attempt at the lower energy fails, one should repeat the 15-J conversion attempt for a DFT+. If the attempt at 10 J succeeds, one could stop testing and implant the device, since successes

at both 15 and 10 J are more conservative than DFT+ with 2 conversion attempts at 15 J. Addendum: The promising results of the LEET study were accomplished exclusively with ‘‘cold can’ systems, i.e., without using the pulse generator as part of the defibrillation electrode configuration. It appears from many studies that the “hot can” systems generally lower defibrillation energy requirements. Thus, it seems probable that LEET, applied to such hot can systems, could allow adequate safety margins with even lower energies. We are in fact currently investigating this hypothesis, carrying out a similar study, combining the hot can with the Endotak lead.

APPENDIX Low Ene~” Endotak Trial (LEET) Investigators:U. The

Ganschow, MD, Department of Cardiology, University Hospital, Dusseldorf; A. Heisel, MD, Department of Cmdiology, University Hospital, Homfrurg/Saar; E. Himrnrich, MD, Department of Cardiology, University Hospital, Mainz; J. Jung, MD, Department of Cardiology, University Hospital, Homburg/Saar; A. Liebrich, MD, Department of Cardiology, University Hospital, Mainz; J. Nerrzrrer, MD, Department of Cardiology, Kercfdroff KJinik, Bad Nauheim; H. F. Pitscbner, MD, Department of Cardiology, Kerckhoff KJinik, Bad Akzaheim; E. G. Vester, MD, Department of Cardiology, University HospitaJ, Dtissddmf.

Acknowledgment The author wishes to acknowledge Drs. S. Sen (Frankfurt) and N. Treese (Osnabfick), who made important contributions in the start-up phase of the study; Professors E. Robles de Medina (Utrecht) and H. Klein (Magdeburg), who provided valuable counsel as members of the Data and Safety Monitoring Committee; and Ulrich Michel, CPI Germany, for his technical support throughout the study.

1. Mirowski M, Reid P, Mower MM, Watkins L, Gott VL, Schauble JF, Langer A, Heilman MS, Kolenik SA, Fischell RE, Weisfeldt ML Termination of maIignant ventricular arrhythmias with an implanted automatic defibrillator in human beings. N Engl J Med 1980;303:322–324. 2. Winkle RA, Mead RH, Ruder MA, Ga.diani VA, Smith NA, Buch WS, Schmidt P, Shipman T. Long-term outcome in patients receiving an automatic implantable cardioverter/defibrillator. JAm COZ1CardioJ 1989;14:508-514.

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29. Neuzrrer J, Pitschuer HF. Stohciug R, Reinisch P, Schlepper M. Implantierbare Kardioverter/Defibrillaturen fit endukardialen Elektmrtensystemen: Lmrgfristige Stabilitiit der DefrbrillationseffektivitJit. ZKardiol 1995;84:44-50. 30. Poule JE, Bardy GH, Dolack GL, Kudenchuk PJ, Anderson J, Johnson G, Serial defibrillation threshold meaaares in man: a prospective controlled study. J Cardirwasc Electrophysiol 1995;6:19-25. 31. Pinski SL, Vanerio G, Castle LW, Morant VA, Simmons TW, Trohman G, Wilcoff BL, Maloney JD. Patients with a high defibrillation threshold: clinical chameteristics, management and outcume. Am Heart J 1991;122:89-95. 32. Epsteiu AE, Ellenbogen KA, Kick KA, Kay GN, Dailey SM. Plumb VJ, and the High Defibrillation Threshold Investigators. Clinical characteristics and outcome uf patients with high defibrillation thresholds. ’A multicenter study. Circulation 1992;86:1206-1216. 33. Neazner J, Pitschner HF, Kttnig S, St6hring R, Schlepper M, Stored electrograms in cardioverter/defibriRator tJrerapy: accamcy of rhythm diagnosis in 335 sprmtaneous arrbytbmia episodes. .JAm Monitoring 1995;8:1–9. 34. Block M, Breithardt G. Relationship between acute defibrillation threshold tinting and therapy outcome. In: Canrm J, Lindemans FW, eds, Transvenous Defibrillation aud Radiofrequency Ablation. Armonk, NY: Futura, 1995:105117.

DISCUSSION Dr. Block (Munster,Germany): Congratulations on this fascinating talk and to the LEET group for designing this very important study as long as 3 years ago. From our own data after 3 years of follow-up and measurement of the defibrillation threshold (DFT) at time of device replacement, I think that in a DFT range of 5–20 J, it is better to use an absolute safety margin. Your data similarly showed the lowest success rate with 5 J and the highest with 15–20 J, so I believe that a relative safety margin is not ideal. Dr. Neuzner (Bad Nauheim, Germany): The success rate for 5 J versus 15 J depends statistically on the method of step-down testing. Higher energy levels have a higher probability for success, of course. It is our policy to test these 2 X DFT protocols even during routing ICD implantation. If a 1O-J shock fails, we don’t give a 34-J rescue shock, but rather 2 x DIT (20 J) to get more information regarding the dose–response curve. I think, when devices get smaller, with 10–20 J outputs, it will be very difficult to extrapolate the results of a 30-J device with a 1O-Jsafety margin to such lower energy devices. Relative to a 1O-J DFT, a 20-J device provides a 100% increase of 10 J, absolute. For a 20-J DFT with a 34-J device, you have percentage-wise a lower safety margin, despite a higher absolute safety margin. This concept allows you to identify patients suitable for implantation with smaller devices. As Dr. Winter s~d, 5% of the patients are problematic and will need higher output devices. But based on our clinical experience, theoretically a 20-J device should suffice for >40% of patients, even with present technology. Dr. Jordaens (Ghent, Belgium): Both arms of your trial had 1 sudden death, a little > 1%. Do you have any further information on the mode of these 2 sudden deaths? Dr. Neuzner: In 1 patient, during a repetitive cluster of ventricular fibrillation. The second was found dead and not really documented.

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