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Circulation. 1995;92:3273-3281

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(Circulation. 1995;92:3273-3281.)
© 1995 American Heart Association, Inc.

Articles

Influence of the Implantable Cardioverter/Defibrillator on Sudden Death and Total Mortality in Patients Evaluated for Cardiac Transplantation

Michael O. Sweeney, MD; Jeremy N. Ruskin, MD; Hasan Garan, MD; Brian A. McGovern, MD; Mary L. Guy, RN; David F. Torchiana, MD; Gus J. Vlahakes, MD; John B. Newell, BA; Marc J. Semigran, MD; G. William Dec, MD

From the Cardiac Arrhythmia Service (M.O.S., J.N.R., H.G., B.A.M., M.L.G.), Cardiac Surgical Service (D.F.T., G.J.V.), Cardiac Computer Center (J.B.N.), and Heart Failure/Transplantation Service (M.J.S., G.W.D.), Massachusetts General Hospital, Harvard Medical School, Boston, Mass.

Correspondence to Dr G.W. Dec, Heart Failure/Transplantation Service, Massachusetts General Hospital, Boston, MA 02114.


*    Abstract
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Background Implantable cardioverter/defibrillators (ICDs) may reduce sudden tachyarrhythmic death in patients with severe left ventricular dysfunction. It is uncertain whether this improves survival, particularly in patients awaiting cardiac transplantation.

Methods and Results The effect of treatment for spontaneous ventricular arrhythmias (ICD [n=59], antiarrhythmic drugs [n=53], or no antiarrhythmic treatment [n=179]) on total mortality and mode of cardiac death was analyzed in 291 consecutive patients evaluated for cardiac transplantation between January 1986 and January 1995. There were 109 deaths (37.4%) (63 [21.6%] sudden, 40 [13.7%] nonsudden, and 6 [2.1%] noncardiac) during mean follow-up of 15 months (range, 1 to 118 months). Baseline clinical variables, medical therapies for heart failure, and actuarial rates of transplantation were similar between treatment groups. Kaplan-Meier sudden death rates were lowest in the ICD group, intermediate in the no antiarrhythmic treatment group, and highest in the drug treatment group throughout follow-up (12-month sudden death rates, 9.2%, 16.0%, and 34.7%, respectively; P=.004). Total mortality and nonsudden death rates did not differ. Cox proportional-hazards model revealed that antiarrhythmic drug treatment was associated with sudden death (relative risk, 2.1; 95% CI, 1.04 to 3.39; P=.04) and ICD was associated with nonsudden death (relative risk, 2.26; 95% CI, 1.12 to 4.62; P=.02).

Conclusions Sudden death rates were lowest in patients treated with ICDs compared with drug treatment or no antiarrhythmic treatment. However, although ICDs reduced sudden death in selected high-risk patients with severe left ventricular dysfunction, the effect on long-term survival was limited, principally by high nonsudden death rates.


Key Words: death, sudden • heart failure • transplantation


*    Introduction
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Sudden cardiac death constitutes a major threat to survival in advanced chronic heart failure.1 As many as 25% to 40% of patients awaiting cardiac transplantation die suddenly.2 3 The mechanisms of sudden death in this clinical setting are diverse and include ventricular tachyarrhythmias, bradyarrhythmias, and nonarrhythmic causes.4 Stratification of sudden death risk in this population is problematic, since clinical variables do not reliably distinguish between risks of sudden and nonsudden death and are more realistically viewed as nonspecific predictors of total cardiac mortality.4 5 6 7 8 Although medical therapies have been shown to improve survival in advanced chronic heart failure,9 10 11 12 cardiac transplantation represents the best hope for long-term survival in many of these patients. However, transplantation is limited largely by donor availability.13 14 Furthermore, many patients are not suitable candidates for transplantation because of advanced age or additional illness.

Several studies have examined the factors that limit survival in patients evaluated for cardiac transplantation.15 16 17 18 The implantable cardioverter/defibrillator (ICD) has been shown to effectively reduce sudden death due to ventricular tachyarrhythmias across wide subsets of patients, including those with severe left ventricular dysfunction.19 20 It has been suggested that the ICD may serve as a "bridge" to cardiac transplantation by reducing sudden tachyarrhythmic death in high-risk patients.21 22 23 However, considerable controversy exists as to whether the reduction in sudden death due to ventricular tachyarrhythmias yields improved overall survival in patients with severe left ventricular dysfunction.24 25 26 27 28 Some authorities have argued that the ICD merely saves such patients to die imminently of end-stage heart failure.27 29

We retrospectively analyzed total mortality, sudden cardiac death, and nonsudden cardiac death in 291 consecutive patients with advanced chronic heart failure referred for cardiac transplantation evaluation. We compared three groups based on treatment for spontaneous ventricular arrhythmias at the time of initial transplantation evaluation: ICD, antiarrhythmic drug treatment, or no antiarrhythmic treatment. The effects of these treatments on mode of cardiac death and total mortality were examined.


*    Methods
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Patients
The study population consisted of 291 consecutive patients referred for cardiac transplantation evaluation at the Massachusetts General Hospital between January 1986 and January 1995. Patients who met criteria for consideration of transplantation (severe symptomatic heart failure despite intensive medical therapy and without a reversible cause, age <62 years, creatinine clearance >50 mL/min, absence of contraindications to long-term immunosuppression, and no other life-threatening medical illnesses) underwent formal transplantation evaluation. This included comprehensive history and physical examination, resting 12-lead ECG, ambulatory ECG (Holter monitoring), pulmonary function testing, exercise stress testing with oxygen uptake determination, transthoracic echocardiogram and/or radionuclide gated blood pool scan, and right and left heart cardiac catheterization.

Baseline Variables
Baseline variables at the time of initial transplantation evaluation are listed in Table 1Down. Significant coronary artery disease was defined as any single stenosis >70% of the cross-sectional luminal diameter of the involved artery.


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  		Table 1. Baseline Clinical Characteristics of 291 Consecutive Patients Referred for Cardiac Transplantation Evaluation

Classification of Spontaneous Ventricular Arrhythmias
All patients had spontaneous ventricular arrhythmias (defined as ventricular premature beats) documented by resting or exercise ECGs, continuous ECG monitoring while hospitalized, or ambulatory ECG (Holter) monitoring. For the purpose of analysis, no effort was made to systematically grade ambient ventricular arrhythmias because of the nonstandardized, retrospective collection method. Nonsustained ventricular tachycardia was defined as >=3 consecutive ventricular premature beats at rates >=100 beats per minute, lasting <30 seconds. Sustained ventricular tachycardia was defined as ventricular tachycardia at rates >=100 beats per minute and requiring an intervention for termination. Cardiac arrest was defined as sudden loss of consciousness resulting from a ventricular tachyarrhythmia and requiring cardiopulmonary resuscitation, including external DC shock, for termination.

Classification of Patients Based on Treatment for Ventricular Arrhythmias
Treatment for spontaneous ventricular arrhythmias was nonrandomized. The severity of symptoms attributable to ventricular arrhythmias (in particular, cardiac arrest and syncope due to sustained ventricular tachycardia) was the principal determinant of antiarrhythmic treatment. Differences between treatment groups are summarized in Table 1Up.

ICD group. Fifty-nine patients were treated with ICDs. Twenty-five patients (42.4%) had ICDs implanted before transplantation evaluation; 34 (57.6%) received implants at the time of transplantation evaluation. The reasons for ICD implantation were (1) out-of-hospital cardiac arrest and absence of inducible ventricular arrhythmias at baseline electrophysiological testing (7 patients, 11.9% of the group); (2) out-of-hospital cardiac arrest and either persistently inducible ventricular tachycardia or ventricular fibrillation despite multiple antiarrhythmic drugs (20 patients, 33.4% of the group) or ICD as first-line therapy (11 patients, 18.6% of the group); (3) spontaneous nonsustained or sustained ventricular tachycardia and either persistently inducible sustained ventricular tachycardia despite multiple antiarrhythmic drugs (7 patients, 11.9% of the group) or ICD as first-line therapy (5 patients, 8.5% of the group); and (4) syncope and either persistently inducible sustained ventricular tachycardia despite multiple antiarrhythmic drugs (4 patients, 6.8% of the group) or ICD as first-line therapy (5 patients, 8.5% of the group).

All ICD patients were instructed to notify their cardiologist in the event of a spontaneous shock. In addition, they were routinely seen at 3- to 4-month intervals, at which time the device was interrogated and a spontaneous shock history (circumstances and premonitory symptoms, if any) was recorded. Twenty-four patients had first- or second-generation devices capable of tabulating spontaneous shocks but unable to store any information regarding the clinical event (Intec AID; CPI AICD 1500, 1520, 1550, 1555, 1600), and 35 patients had third-generation devices with the ability to retrieve intracardiac electrograms and tachycardia cycle lengths (Ventritex V-100 Cadence; CPI 1620 P2; Medtronic 7219 Jewel) or tachycardia cycle lengths alone (Medtronic 7217 PCD, CPI 1700/1705 PRx) before and after delivered therapy. Nonthoracotomy defibrillation lead systems were used in 19 patients (32.2%), and 40 patients (67.8%) underwent thoracotomy for implantation of defibrillation electrodes.

Antiarrhythmic drug treatment group. Fifty-three patients were receiving antiarrhythmic drug treatment at the time of transplantation evaluation and during follow-up. Twenty-six patients (49.1%) had prior out-of-hospital cardiac arrests (14 patients, 26.4%) or syncope due to sustained ventricular tachycardia (12 patients, 22.6%); 27 patients (50.1%) received drug treatment for mildly symptomatic (palpitations, lightheadedness) nonsustained ventricular tachycardia (Table 1Up). Thirty-nine patients (73.6% of the group) received Holter-guided drug treatment, and 14 patients (26.4% of the group) received drug treatment guided by serial electrophysiological testing. The antiarrhythmic drugs used were (1) class IA, 17 patients (32.1%); (2) class IB, 6 patients (11.3%); (3) class IA and IB, 3 patients (5.7%); (4) class IC, 5 patients (9.4%); (5) class III (amiodarone), 20 patients (37.7%); (6) sotalol, 1 patient (1.9%); and (7) other combinations, 1 patient (1.9%).

No antiarrhythmic treatment group. The remaining 179 patients did not receive any specific antiarrhythmic treatment. Four patients (2.2%) had out-of-hospital cardiac arrests associated with reversible conditions. Two patients had polymorphic ventricular tachycardia attributed to antiarrhythmic drugs (quinidine in 1 patient, ethmozine in 1 patient), which were subsequently discontinued. One patient had ventricular fibrillation in the setting of severe coronary artery disease (not associated with acute myocardial infarction) that was treated with percutaneous transluminal coronary angioplasty. The fourth patient had ventricular fibrillation in association with severe rheumatic mitral regurgitation and decompensated congestive heart failure and underwent mitral valve replacement.

Follow-up
The mean follow-up period in the study population was 15.8±18.3 months (range, 1 to 118 months) and was completed in all 291 patients. The principal study end points were cardiac transplantation, death before transplantation, or living at most recent follow-up (February 1, 1995).

Mortality End Points
The circumstances surrounding each patient death were determined from hospital records, autopsy reports, and interviews with personal physicians and family members. Deaths were then classified according to the recommendations of the North American Society of Pacing and Electrophysiology30 as sudden cardiac, nonsudden cardiac, operative, or noncardiac. Sudden cardiac deaths met at least one of three criteria: (1) witnessed cardiac arrest; (2) within 1 hour after the onset of acute symptoms; or (3) unexpected, unwitnessed death (ie, during sleep) in a patient known to have been well within the previous 24 hours. Nonsudden cardiac death was defined as death due to progressive congestive heart failure and/or low-output state preceding terminal ventricular tachyarrhythmias (if any). Operative deaths were defined as death within 30 days of attempted ICD implant or before hospital discharge or the direct result of an ICD implant–related complication.

Statistical Analysis
Statistical analyses were performed according to the "intention-to-treat" principle.31 Thus, patients were analyzed in their respective treatment group (ICD, antiarrhythmic drugs, or no antiarrhythmic treatment) at the time of initial transplantation evaluation regardless of cross-over to a different treatment group during follow-up.

Survival was measured from the date of initial transplantation evaluation. Total mortality estimates were calculated by the Kaplan-Meier product limit method32 and included noncardiac deaths, in compliance with the recommendations of the North American Society of Pacing and Electrophysiology.30 Patients who received transplants during follow-up were analyzed as "living" up until that time. Differences between survival curves were analyzed by the generalized Savage (Mantel-Cox) test. The effects of relevant variables on total mortality and mode of cardiac death (sudden or nonsudden) were evaluated with the Cox proportional-hazards model.33 Predicted survival functions were computed for all observations with no missing independent variables. A missing-values test performed before Cox modeling demonstrated no difference in the pattern of missing values between the three treatment groups (ICD, antiarrhythmic drugs, or no antiarrhythmic treatment). For continuous variables, relative risks in the Cox model are reported per unit of measure of the corresponding variable.

Analyses were performed with the BMDP Statistical Software 1993 version. Continuous numerical data are expressed as mean±SD. Comparisons between groups were calculated by {chi}2 analysis or ANOVA, as appropriate. A value of P<.05 (two-tailed) was considered significant.


*    Results
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Baseline Characteristics
Baseline clinical characteristics of the total study population and the three treatment groups are shown in Table 1Up. The majority of patients had either coronary artery disease or idiopathic dilated cardiomyopathy (47.1% and 42.3%, respectively), severely depressed left ventricular systolic function (mean left ventricular ejection fraction, 18.6±9.3%), and advanced symptomatic heart failure (mean New York Heart Association [NYHA] heart failure class 3.4±0.7). Fifty-six percent of the total study population (163 patients) were listed with the New England Organ Bank for cardiac transplantation. The reasons for not listing the remaining 128 patients for transplantation were one or more of the following: considered "too well" at the time of evaluation (15.5%), patient refusal (6.5%), or exclusion due to exigent medical illnesses or advanced age (22.0%).

Baseline variables were similar between groups except for mean age (slightly higher in the drug treatment group); incidence of coronary artery disease (slightly lower in the no antiarrhythmic treatment group); history of prehospital cardiac arrest, syncope due to sustained ventricular tachycardia, and use of ß-blockers (higher in the ICD group); and intracardiac pressures (lower in the ICD group). There was a trend toward shorter mean time from evaluation to transplantation in the ICD group. Importantly, mean time from listing to transplantation was not significantly different among the groups.

Crossover Between Treatment Groups
Three of 291 patients (1.0%) crossed over to different treatment groups during follow-up and were analyzed according to their respective treatment group at the time of initial transplantation evaluation. One patient in the no antiarrhythmic treatment group at initial evaluation experienced syncope due to sustained ventricular tachycardia 3 months later; an ICD was implanted, and the patient successfully received a transplant 1 day later (see "Discussion"). A second patient in the no antiarrhythmic treatment group at initial evaluation developed nonsustained ventricular tachycardia 4 months later; amiodarone was begun, and the patient died suddenly less than 1 month thereafter. One patient in the drug treatment group at initial evaluation had aborted sudden cardiac death due to ventricular fibrillation 6 months later; an ICD was implanted, and the patient successfully received a transplant 11 months thereafter.

Actuarial Total Mortality and Sudden and Nonsudden Cardiac Death for the Entire Study Population and by Treatment Group
Estimated actuarial total mortality, sudden cardiac death, and nonsudden cardiac death rates in the entire study population are shown in Table 2Down and Fig 1Down. The actuarial total cardiac mortality for the entire study population increased progressively throughout follow-up and was 30.2% and 45.5% at 12 and 24 months, respectively.


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  		Table 2. Actuarial Mortality Event Rates During Follow-up



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  		Figure 1. Graph showing total mortality, sudden death, and nonsudden death in 291 patients referred for cardiac transplantation evaluation.

Actuarial total mortality and sudden and nonsudden cardiac death rates for the three treatment groups are shown in Table 2Up and Fig 2Down. There was no statistically significant difference in total mortality between groups throughout follow-up (Fig 2ADown; P=.19). There was a significant difference in sudden cardiac death rates favoring the ICD group (Fig 2BDown; P=.004). The 12-month sudden death rate in the ICD group was 9.1%, versus 34.7% in the drug treatment group and 16.0% in the no antiarrhythmic treatment group. In contrast, cumulative nonsudden cardiac death rates (Fig 2CDown) did not differ among groups (P=.56).



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  		Figure 2. Graphs showing comparison of total mortality (A), sudden death (B), and nonsudden death (C) among the three treatment groups. ICD indicates implantable cardioverter/defibrillator.

There were no operative deaths associated with ICD implantation. Actuarial rates of transplantation were not different between antiarrhythmic treatment groups (data not shown; P=.27).

Predictors of Total Mortality and Sudden and Nonsudden Cardiac Death
The effects of baseline variables on total mortality and sudden and nonsudden cardiac death were evaluated with a multivariate stepwise Cox regression model (Table 3Down). NYHA functional class was the most powerful independent predictor of total mortality (relative risk, 2.14 per increment in functional class, P=.0001). Mean pulmonary capillary wedge pressure was also directly related to total mortality (relative risk, 10.31 per 10 mm Hg, P=.01), and mean cardiac output was inversely related to total mortality (relative risk, 0.78 per liter per minute, P=.007).


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  		Table 3. Variables Associated With Total Mortality, Sudden Cardiac Death, and Nonsudden Cardiac Death: Cox Proportional-Hazards Model

The strongest predictor of sudden cardiac death was mean NYHA functional class (relative risk, 2.63 per increment in functional class, P=.0001). Antiarrhythmic drug treatment was also directly related to sudden cardiac death (relative risk, 2.10, P=.04).

Mean pulmonary capillary wedge pressure was the most powerful predictor of nonsudden cardiac death (relative risk, 10.55 per 10 mm Hg, P=.001). NYHA functional class (relative risk, 2.08 per increment in functional class, P=.005) and presence of ICD (relative risk, 2.26, P=.02) were also directly related to nonsudden cardiac death.

Neither age nor underlying cardiac disease was an independent predictor of total mortality, sudden death, or nonsudden cardiac death despite baseline differences between treatment groups.

Circumstances of Sudden Cardiac Death in the ICD Group
There were five sudden cardiac deaths in the ICD group. All five ICD patients who died suddenly had stable NYHA class III heart failure; one patient was hospitalized, and the remaining four were ambulatory at the time of death. One ambulatory patient died in cardiogenic shock immediately after multiple (>10) successful ICD shocks for documented incessant ventricular tachycardia/fibrillation. A second ambulatory patient died while sleeping; postmortem ICD interrogation revealed 24 new successful shocks for apparent ventricular tachycardia (based on pretherapy and posttherapy tachyarrhythmia cycle length memory), and the final recorded rhythm was ventricular bradycardia pacing. Two ambulatory patients died of electromechanical dissociation with ventricular bradycardia pacing within minutes after successful shocks for documented ventricular tachyarrhythmias. A fifth patient died while hospitalized of unheralded electromechanical dissociation with ventricular bradycardia pacing (ie, not preceded by shocks for ventricular tachyarrhythmias or acute decline in heart failure clinical status).

Total Mortality and Sudden and Nonsudden Cardiac Death in Patients Listed and Awaiting Transplantation
Total mortality did not differ by antiarrhythmic treatment among those patients listed and awaiting transplantation (Fig 3ADown, P=.83). In contrast to the analysis of the study population as a whole, sudden cardiac death rates (Fig 3BDown) were not statistically different among the treatment groups (P=.89). Similarly, nonsudden cardiac death rates (Fig 3CDown) did not differ among groups (P=.93).



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  		Figure 3. Graphs showing comparison of total mortality (A), sudden death (B), and nonsudden death (C) among the three treatment groups among patients listed and awaiting transplantation. ICD indicates implantable cardioverter/defibrillator.


*    Discussion
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*Discussion
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Sudden Cardiac Death in Advanced Heart Failure
Despite the presence of severe left ventricular dysfunction, the ICD had a significant effect on sudden death in this high-risk population. Actuarial sudden death rates were lowest in patients treated with ICDs and highest in patients treated with antiarrhythmic drugs (9.2% versus 34.7% at 12 months, respectively) throughout follow-up. Patients who received no antiarrhythmic treatment for ventricular arrhythmias had an intermediate but nonetheless significant rate of sudden death (16.0% at 12 months). The most powerful independent predictor of sudden death in the multivariate Cox regression model was NYHA functional class at time of transplantation evaluation; however, this variable was also an independent predictor of nonsudden cardiac death and total mortality. Importantly, antiarrhythmic drug treatment was also a significant independent predictor of sudden death. These data, although uncontrolled, are compatible with accumulating evidence that long-term antiarrhythmic therapy in patients with significant structural heart disease and ventricular arrhythmias is associated with increased mortality, most likely because of drug-related fatal arrhythmias.34

Sudden Death in ICD Patients
All of the ICD sudden deaths in this series occurred in patients with third-generation devices and ventricular bradycardia pacing capabilities. In four of five cases, the initial ventricular rhythm recorded immediately after sudden collapse was ventricular bradycardia pacing with electromechanical dissociation. Sudden death due to bradyarrhythmias or electromechanical dissociation is a well-described phenomenon in patients with advanced heart failure and may be more common in idiopathic dilated cardiomyopathy.35 36 The ICD is intended solely to treat rapid ventricular arrhythmias and therefore would not be expected to have any direct effect on sudden bradyarrhythmic death. Furthermore, there is as yet no evidence to suggest that ventricular pacing can rescue patients from sudden bradyarrhythmic death in the setting of advanced left ventricular dysfunction.

Two of the sudden bradyarrhythmic deaths in this ICD series were immediately preceded by successful termination of ventricular tachycardia or ventricular fibrillation by high-energy shocks. Additionally, three surviving patients had repeated, transient postshock ventricular asystole and electromechanical dissociation with ventricular pacing during ICD defibrillation threshold testing. In each case, cardiopulmonary resuscitation was performed for 1 to 3 minutes until hemodynamic and electrical recovery occurred. Two patients remained hospitalized until transplantation; one patient elected to await transplantation on an outpatient basis against medical advice. The frequency with which this phenomenon (postshock electromechanical dissociation) may account for sudden deaths in ICD patients with advanced left ventricular dysfunction, despite successful termination(s) of ventricular tachyarrhythmias, is unknown.

Mortality Due to Progressive Heart Failure
Actuarial nonsudden cardiac death rates were not significantly different among the three antiarrhythmic treatment groups. This is not surprising, because there were no significant differences for relevant clinical variables, including mean NYHA functional class, left ventricular ejection fraction, heart failure therapy, proportion listed for transplantation, mean time until transplantation, or actuarial rate of transplantation.

Pulmonary capillary wedge pressure (relative risk, 10.55 per 10 mm Hg, P=.001) and NYHA functional class (relative risk, 2.08 per increment in functional class, P=.005) were directly related to risk of nonsudden cardiac death. These findings are consistent with previous reports.15 16 17 18 Interestingly, the presence of an ICD was also a significant multivariate predictor of nonsudden cardiac death (relative risk, 2.26, P=.02). This implies that the reduction in sudden cardiac death resulted in an increased likelihood of nonsudden cardiac death in ICD patients, which were reciprocal dependent variables in the regression model.

Total Mortality
Despite the marked reduction of sudden tachyarrhythmic death in ICD patients in the present study, total mortality was not different among the three treatment groups. There are several possible explanations for these results. First, this study may have lacked sufficient power (type II error) to detect a true difference in mortality, which is likely to be limited in ICD patients with advanced heart failure.26 37 Second, there may have been unrecognized subtle selection biases in the ICD patients that resulted in higher nonsudden cardiac death rates. Previous studies, primarily in out-of-hospital cardiac arrest survivors, have shown that the ICD confers a time-dependent survival benefit compared with guided drug therapy that varies directly with the degree of left ventricular dysfunction.38 39 40 Total survival was uniformly worse in those ICD patients with poor left ventricular function.38 39 40 This explanation seems unlikely in the present study, however, since baseline variables shown to be predictive of total mortality and nonsudden cardiac death were either no different between groups or biased in favor of the ICD group (ie, lower baseline intracardiac pressures). Additionally, although it seems counterintuitive that a reduction in sudden death rates might not result in a parallel reduction in total mortality, this possibility exists when actuarial methods are used to estimate survival in ICD patients.37 This phenomenon has been called "conversion" of the mode of death and is cited by some authorities as a partial explanation for the failure of the ICD to reduce total mortality to the extent initially envisioned.24 27 The limitation of the "conversion" concept is that it implicitly considers the patient at the time when recurrent ventricular arrhythmias presage imminent demise due to end-stage heart failure. Measured at only this point in time, the "survival benefit" of the ICD would appear to be minimal. A more dynamic long-term process is suggested by this study. The marked reduction in sudden death rates in the ICD group appears to be negated by higher nonsudden death rates throughout follow-up. The net effect of reduced sudden death on total mortality is thereby continuously marginalized.

Mortality in Patients Listed and Awaiting Transplantation
As in the study population as a whole, total mortality and nonsudden death rates did not differ between treatment groups among the subpopulation with the poorest clinical and hemodynamic status, ie, those patients listed and awaiting transplantation (Fig 3AUp: total mortality, P=.83; Fig 3CUp: nonsudden death, P=.93, respectively). In contrast to lower sudden death rates in the ICD group compared with the other two treatment groups for the entire study population, this effect was not observed in the subpopulation of patients awaiting transplantation (Fig 3BUp, P=.89). Although this lack of reduction in sudden death rates in the ICD patients may again reflect the effect of small sample size and limited power to detect significant differences between treatment groups, it may also be due to the influence of sudden bradyarrhythmic deaths. There were five sudden deaths in the ICD group overall; four occurred in patients awaiting transplantation. In all four cases, the initial recorded rhythm immediately after sudden collapse was ICD ventricular pacing with surface ECG noncapture or failure to maintain peripheral pulse and blood pressure despite ECG capture (ie, electromechanical dissociation).

Stratification of Sudden Death Risk in Advanced Chronic Heart Failure
The relative frequency of sudden death in chronic heart failure has previously been reported to range from 25% to 40% in patients awaiting transplantation,2 3 to 50% in patients with milder symptoms.41 The association between spontaneous ventricular arrhythmias and left ventricular dysfunction as independent and multiplicative risk factors for total cardiac death is well established.5 6 However, these and other clinical variables do not reliably discriminate risk of sudden death from overall risk of cardiac mortality in patients with chronic heart failure.1 5 6 7 8 14 42 High-resolution electrocardiography43 and electrophysiological testing44 are only modest predictors of sudden death risk in patients with chronic heart failure due to coronary artery disease and probably have little utility in patients with idiopathic dilated cardiomyopathy. Electrophysiologically guided drug therapy in survivors of cardiac arrest with at least moderate heart failure is limited by a significantly lower likelihood of arrhythmia suppression, unreliability of programmed stimulation in certain clinical subsets (ie, idiopathic dilated cardiomyopathy), reduced drug treatment options imposed by heart failure, and early drug breakthrough despite initial suppressibility.45 Empirical drug therapy is unjustified and probably dangerous,4 46 47 48 with the possible exception of amiodarone.49 50 51 52

The only apparent difference between patients who died suddenly during follow-up and those who did not in the present study was the frequency or severity of symptomatic spontaneous ventricular arrhythmias (including aborted sudden death) that prompted ICD or drug treatment antemortem. Thus, it may be most rational to think of similar patients with advanced heart failure as existing at different points along the same time continuum for sudden arrhythmic death. The concept of sudden death risk stratification based on conventional variables (with the exception of prior aborted sudden death or unexplained syncope, which denote an exceedingly high future risk) in patients with advanced heart failure should probably be discarded. The occurrence of sudden death is almost certainly a nonlinear or "chaotic" function and possibly random. In either case, it is beyond the resolution of contemporary predictive techniques on a patient-specific basis.

Implications for Empirical ICD Therapy in Patients Awaiting Cardiac Transplantation
Previous reports have suggested a possible role for the empirical use of ICDs to reduce sudden death in heart transplantation candidates.21 22 23 The multicenter DEFIBRILAT (DEFIbrillator as BRIdge to LAter Transplantation) trial was conceived to explore this hypothesis but was terminated before any patients were enrolled because of lack of funding (M. Lehman, MD, personal communication).

This study exposes several unique limitations of ICD therapy in the pretransplant population. The timing of sudden death while the patient is awaiting transplantation, as well as the timing of availability of a suitable donor heart, cannot be predicted on an individual patient basis. These realities present formidable problems for patient-specific management, as highlighted by two vignettes from the present study. A 49-year-old ambulatory male patient with stable NYHA class III ischemic cardiomyopathy and no prior history of lethal ventricular arrhythmias was placed on the outpatient transplantation waiting list. Less than 24 hours later, he died suddenly of a witnessed ventricular fibrillation arrest (in the absence of acute myocardial infarction). In contrast, a 48-year-old ambulatory male with similarly stable NYHA class III ischemic cardiomyopathy had aborted sudden cardiac death due to sustained ventricular tachycardia after 3 months on the outpatient transplantation waiting list. Electrophysiological testing induced rapid, sustained, uniform ventricular tachycardia, and an ICD was implanted. One day later, while the patient was recovering from successful ICD implantation, a donor heart became available, and the patient underwent transplantation.

Additionally, 5.1% (3/59) of the ICD patients had hemodynamic collapse and prolonged electromechanical recovery after high-energy defibrillation shocks during ICD implantation. It is unknown whether such individuals would survive spontaneous ICD shocks as outpatients, despite successful termination of ventricular tachycardia or fibrillation. Furthermore, sudden deaths in ICD patients (including those awaiting transplantation in the present report) appear to be mainly bradycardic, may occur shortly after successful shocks for ventricular tachyarrhythmias, and appear not to be prevented by backup ventricular pacing available in tiered-therapy devices.53 These phenomena might erode the impact of the ICD as a sudden death "safety net" in the ambulatory population awaiting transplantation.

Limitations of the Present Study
There are several important limitations of this study. It was retrospective, and the treatment of ventricular arrhythmias was uncontrolled and nonrandomized. The ICD patients were highly selected; the majority were cardiac arrest survivors whose arrhythmias could not be suppressed with multiple antiarrhythmic drug regimens or in whom ventricular tachyarrhythmias could not be induced at baseline electrophysiological testing. The use of any antiarrhythmic drug other than amiodarone, in the setting of severe left ventricular dysfunction, is potentially hazardous and may have biased the primary mortality end points against the drug treatment group. The majority of patients (61%) did not receive any specific antiarrhythmic treatment. Autopsy data were unavailable in the vast majority of deaths; therefore, the exact mechanism of death could not be determined with certainty. Recent investigation has shown that sudden death rate estimates, in particular, may be dramatically altered by autopsy results.54

Conclusions
This study demonstrates that the ICD can profoundly alter the mode of cardiac death in patients with advanced heart failure. The marked reduction in sudden death due to ventricular tachyarrhythmias engenders the uninterrupted progression of the underlying disease process. This "unnatural" history poses a unique dilemma by the creation of a novel population of patients with progressively advancing heart failure and a relatively low incidence of sudden death. Despite compelling evidence that the ICD can effectively reduce sudden death in some patients with severe left ventricular dysfunction, including those awaiting transplantation, this study raises important questions regarding the ultimate survival benefit in this population. This is underscored by the soberingly high rates of heart failure death, bradyarrhythmic sudden death, and total mortality in the ICD patients who did not receive transplants. The use of the ICD in patients with advanced heart failure appears most appropriate for those with a realistic chance of transplantation.

Received November 7, 1994; revision received June 13, 1995; accepted July 17, 1995.


*    References
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*References
 

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